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Sample records for acute immunological lung

  1. 7. Immunologic lung disease.

    PubMed

    Greenberger, Paul A

    2008-02-01

    The lung is an extremely complex organ and participates in initial responses to inhaled antigens, infectious agents, and irritants or as a response to exposure through the oral, parenteral, or transdermal routes. There can be constriction of the airways or involvement or even destruction of the lung parenchyma, depending on the condition. This review focuses on selected aspects of the pulmonary innate and adaptive immune responses; the new condition World Trade Center cough, which can cause an asthma-like presentation and resemble reactive airways dysfunction syndrome; and the diagnosis and treatment of various immunologic lung conditions. Innate immune responses occur in the acute respiratory distress syndrome and in transfusion-related acute lung injury. Adaptive immune responses involve specialized mucosal and systemic immune responses, lymphocytes, and antibodies and can result in CD4+ TH1 and TH2 phenotypes, such as TH1 for tuberculosis and TH2 for asthma. PMID:18241689

  2. Immunologic lung disease

    SciTech Connect

    Harman, E.M.

    1985-07-01

    The term immunologic lung disease comprises a broad spectrum of disease. The authors have covered a few entities in which recent studies have been particularly helpful in elucidating pathophysiology though not in uncovering the inciting cause. Common to all of these entities is the problem of finding appropriate methods of defining disease activity and response to treatment. As exemplified by the improved outlook for Goodpasture's syndrome with elucidation of its underlying immunopathology, it is likely that better understanding of the immunologic basis of sarcoid and interstitial disease may be helpful in planning more effective treatment strategies. 44 references.

  3. Chapter 17: Occupational immunologic lung disease.

    PubMed

    Sabin, Bradley R; Grammer, Leslie C

    2012-01-01

    Occupational immunologic lung disease is characterized by an immunologic response in the lung to an airborne agent inhaled in the work environment and can be subdivided into immunologically mediated occupational asthma (OA) and hypersensitivity pneumonitis (HP). Irritant-induced OA, a separate nonimmunologic entity, can be caused by chronic exposure to inhaled irritants or reactive airways dysfunction syndrome, defined as an asthma-like syndrome that persists for >3 months and occurs abruptly after a single exposure to a high concentration of an irritating industrial agent. High-risk fields for OA include farmers, printers, woodworkers, painters, plastic workers, cleaners, spray painters, electrical workers, and health care workers. OA can be triggered by high molecular weight (HMW) proteins that act as complete allergens or low molecular weight (LMW) sensitizers that act as haptens. HMW proteins (>10 kDa) are generally derived from microorganisms (such as molds and bacteria, including thermophilic actinomycetes), plants (such as latex antigens and flour proteins), or animals (such as animal dander, avian proteins, and insect scales) and are not specifically regulated by the Occupational Safety and Health Administration (OSHA). LMW haptens that bind to proteins in the respiratory mucosa include some OSHA-regulated substances such as isocyanates, anhydrides, and platinum. HP can present in an acute, a chronic, or a subacute form. The acute, subacute, and early chronic form is characterized by a CD4(+) T(H)1 and CD8(+) lymphocyte alveolitis. Classically, the bronchoalveolar lavage will show a CD4/CD8 ratio of <1. PMID:22794690

  4. Effects of acute single intranasal instillation of secondary organic aerosol on neurological and immunological biomarkers in the brain and lung of BALB/c mice.

    PubMed

    Win-Shwe, Tin-Tin; Fujitani, Yuji; Sone, Hideko; Furuyama, Akiko; Nitta, Hiroshi; Hirano, Seishiro

    2013-02-01

    Recently, we have reported that primary particles from diesel exhaust affect nervous system, immune system, and learning ability in mice. Currently, in vivo and in vitro studies have shown that secondary organic aerosol (SOA) generated from the coal-fired power plant induced adverse effects in lung and heart. However, the effect of SOA on central nervous system is still unknown. In the present study, using potential biomarkers recognized in previous studies of primary particles, we investigated the effect of acute single administration of SOA on the expression levels of various biomarkers in the brain and lung of mice. We generated the SOA by addition of ozone (O(3)) to the diesel exhaust particle (DEP). Eight-week-old male BALB/c mice were administered DEP or DEP+O(3) (SOA) (50 µg/50 µl/mouse) intranasally. Twenty-four hour after acute single exposure to SOA, olfactory bulb, hippocampus and lung from all mice were collected and mRNA expressions of neurological and immunological biomarkers were examined using real-time RT-PCR analysis and histological examination. Proinflammatory cytokines, their transcription factor and neurotrophin mRNA were remarkably increased in lung of mice exposed to SOA but not in the brain. Microarray data showed that changes of the inflammatory reaction and metabolizing enzyme gene cluster were observed in the brain and lung. Our findings suggested that an acute single exposure of SOA does not affect biomarkers in the brain of normal healthy individuals. Our present results also clearly indicate that SOA induces inflammatory responses in the lung by modulating proinflammatory cytokines, transcription factor and inflammatory responsive neurotrophins. PMID:23358141

  5. The Impact of Antiretroviral Therapy on Lung Immunology.

    PubMed

    Cribbs, Sushma K; Fontenot, Andrew P

    2016-04-01

    Despite the introduction of antiretroviral therapy (ART), human immunodeficiency virus-1 (HIV) continues to cause a major impact worldwide. HIV-induced lung disease continues to represent a significant source of morbidity and mortality, although the spectrum of pulmonary diseases has changed. HIV significantly affects the lung, causing acute and chronic cellular changes in the alveolar space. The impact of ART on lung immunology still needs to be fully elucidated. Similar to the periphery, ART affects HIV viral load and reconstitutes CD4(+) T cells in the lung. ART has been associated with significant decreases in bronchoalveolar lavage lymphocytes and increases in B-cell numbers and functionality, resulting in improved immune responses to vaccinations. There are substantial clinical implications of these ART-induced alterations, including the emergence of immune reconstitution inflammatory syndrome and the increased incidences of noninfectious lung diseases, such as lung cancer and chronic obstructive lung disease. There continues to be many unanswered questions regarding the effects of ART on lung health and, in particular, the immune system. Growing knowledge in this area will hopefully diminish the incidence of these noninfectious lung diseases and further improve the health of individuals living with HIV. PMID:26974295

  6. Acute Lung Failure

    PubMed Central

    Mac Sweeney, Rob; McAuley, Daniel F.; Matthay, Michael A.

    2013-01-01

    Lung failure is the most common organ failure seen in the intensive care unit. The pathogenesis of acute respiratory failure (ARF) can be classified as (1) neuromuscular in origin, (2) secondary to acute and chronic obstructive airway diseases, (3) alveolar processes such as cardiogenic and noncardiogenic pulmonary edema and pneumonia, and (4) vascular diseases such as acute or chronic pulmonary embolism. This article reviews the more common causes of ARF from each group, including the pathological mechanisms and the principles of critical care management, focusing on the supportive, specific, and adjunctive therapies for each condition. PMID:21989697

  7. Acute lung injury review.

    PubMed

    Tsushima, Kenji; King, Landon S; Aggarwal, Neil R; De Gorordo, Antonio; D'Alessio, Franco R; Kubo, Keishi

    2009-01-01

    The first report of acute respiratory distress syndrome (ARDS) was published in 1967, and even now acute lung injury (ALI) and ARDS are severe forms of diffuse lung disease that impose a substantial health burden all over the world. Recent estimates indicate approximately 190,000 cases per year of ALI in the United States each year, with an associated 74,500 deaths per year. Common causes of ALI/ARDS are sepsis, pneumonia, trauma, aspiration pneumonia, pancreatitis, and so on. Several pathologic stages of ALI/ARDS have been described: acute inflammation with neutrophil infiltration, fibroproliferative phase with hyaline membranes, with varying degrees of interstitial fibrosis, and resolution phase. There has been intense investigation into the pathophysiologic events relevant to each stage of ALI/ARDS, and much has been learned in the alveolar epithelial, endobronchial homeostasis, and alveolar cell immune responses, especially neutrophils and alveolar macrophages in an animal model. However, these effective results in the animal models are not equally adoptive to those in randomized, controlled trials. The clinical course of ALI/ARDS is variable with the likely pathophysiologic complexity of human ALI/ARDS. In 1994, the definition was recommended by the American-European Consensus Conference Committee, which facilitated easy nomination of patients with ALI/ARDS for a randomized, clinical trial. Here, we review the recent randomized, clinical trials of ALI/ARDS. PMID:19420806

  8. Hyperoxic Acute Lung Injury

    PubMed Central

    Kallet, Richard H; Matthay, Michael A

    2013-01-01

    Prolonged breathing of very high FIO2 (FIO2 ≥ 0.9) uniformly causes severe hyperoxic acute lung injury (HALI) and, without a reduction of FIO2, is usually fatal. The severity of HALI is directly proportional to PO2 (particularly above 450 mm Hg, or an FIO2 of 0.6) and exposure duration. Hyperoxia produces extraordinary amounts of reactive O2 species that overwhelms natural antioxidant defenses and destroys cellular structures through several pathways. Genetic predisposition has been shown to play an important role in HALI among animals, and some genetics-based epidemiologic research suggests that this may be true for humans as well. Clinically, the risk of HALI likely occurs when FIO2exceeds 0.7, and may become problematic when FIO2 exceeds 0.8 for an extended period of time. Both high-stretch mechanical ventilation and hyperoxia potentiate lung injury and may promote pulmonary infection. During the 1960s, confusion regarding the incidence and relevance of HALI largely reflected such issues as the primitive control of FIO2, the absence of PEEP, and the fact that at the time both ALI and ventilator-induced lung injury were unknown. The advent of PEEP and precise control over FIO2, as well as lung-protective ventilation, and other adjunctive therapies for severe hypoxemia, has greatly reduced the risk of HALI for the vast majority of patients requiring mechanical ventilation in the 21st century. However, a subset of patients with very severe ARDS requiring hyperoxic therapy is at substantial risk for developing HALI, therefore justifying the use of such adjunctive therapies. PMID:23271823

  9. Psychological and immunological correlates of acute overtraining.

    PubMed Central

    Fry, R W; Grove, J R; Morton, A R; Zeroni, P M; Gaudieri, S; Keast, D

    1994-01-01

    Five men undertook two intensive interval training sessions per day for 10 days, followed by 5 days of active recovery. Subjects supplied a venous blood sample and completed a mood-state questionnaire on days 1, 6, 11 and 16 of the study. Performance capabilities were assessed on days 1, 11 and 16 using a timed treadmill test to exhaustion at 18 kmh-1 and 1% grade. These individuals became acutely overtrained as indicated by significant reductions in running performance from day 1 to day 11. The overtrained state was accompanied by severe fatigue, immune system deficits, mood disturbance, physical complaints, sleep difficulties, and reduced appetite. Mood states moved toward baseline during recovery, but feelings of fatigue and immune system deficits persisted throughout the study. PMID:7894955

  10. Alcoholic Lung Injury: Metabolic, Biochemical and Immunological Aspects

    PubMed Central

    Kaphalia, Lata; Calhoun, William J.

    2013-01-01

    Chronic alcohol abuse is a systemic disorder and a risk factor for acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). A significant amount of ingested alcohol reaches airway passages in the lungs and can be metabolized via oxidative and non-oxidative pathways. About 90% of the ingested alcohol is metabolized via hepatic alcohol dehydrogenase (ADH)-catalyzed oxidative pathway. Alcohol can also be metabolized by cytochrome P450 2E1 (CYP2E1), particularly during chronic alcohol abuse. Both the oxidative pathways, however, are associated with oxidative stress due to the formation of acetaldehyde and/or reactive oxygen species (ROS). Alcohol ingestion is also known to cause endoplasmic reticulum (ER) stress, which can be mediated by oxidative and/or non-oxidative metabolites of ethanol. An acute as well as chronic alcohol ingestions impair protective antioxidants, oxidize reduced glutathione (GSH, cellular antioxidant against ROS and oxidative stress), and suppress innate and adaptive immunity in the lungs. Oxidative stress and suppressed immunity in the lungs of chronic alcohol abusers collectively are considered to be major risk factors for infection and development of pneumonia, and such diseases as ARDS and COPD. Prior human and experimental studies attempted to identify common mechanisms by which alcohol abuse directly causes toxicity to alveolar epithelium and respiratory tract, particularly lungs. In this review, the metabolic basis of lung injury, oxidative and ER stress and immunosuppression in experimental models and alcoholic patients, as well as potential immunomodulatory therapeutic strategies for improving host defenses against alcohol-induced pulmonary infections are discussed. PMID:23892124

  11. Immunological and ultrastructural studies in acute biphenotypic leukaemia.

    PubMed Central

    Shetty, V; Chitale, A; Matutes, E; Buccheri, V; Morilla, R; Catovsky, D

    1993-01-01

    AIMS--To compare the sensitivity of the ultrastructural method to detect myeloperoxidase (MPO) with light microscopy and immunocytochemistry using an anti-MPO antibody; to examine the expression of lymphoid antigens in relation to MPO activity in blast cells from cases of biphenotypic leukaemia. METHODS--Blast cells from 14 cases of biphenotypic acute leukaemia were analysed. Immunological markers were performed by single or double immunofluorescence staining on a flow cytometer. The presence of MPO was determined by light microscopy, electron microscopy on fixed and unfixed cells, and by immunoalkaline phosphatase with an anti-MPO antibody. The immunogold method was applied at the ultrastructural level to assess the expression of lymphoid and myeloid antigens at the same time as the MPO activity. RESULTS--Six of the 14 cases were initially classified as acute lymphoblastic leukaemia (ALL) and eight as acute myeloid leukaemia (AML). MPO activity was shown at the ultrastructural level in 4-99% blasts from all cases. Six of the 14 were MPO negative by light microscopy and three of these were negative with the antibody anti-MPO. Coexpression of lymphoid antigens (CD19, CD10, or CD2) and MPO was shown by the immunogold method in four out of 11 cases; in seven cases the blasts coexpressed myeloid antigens (CD13, CD33) and MPO. CONCLUSIONS--Electron microscopy is more sensitive for showing MPO than light microscopy and immunocytochemistry; the immunogold method combined with MPO used at the ultrastructural level can help to define the cell lineage involved in biphenotypic leukaemia by highlighting the myeloid component defined by MPO. Images PMID:8227405

  12. Transfusion-Related Acute Lung Injury: The Work of DAMPs*

    PubMed Central

    Land, Walter G.

    2013-01-01

    Current notions in immunology hold that not only pathogen-mediated tissue injury but any injury activates the innate immune system. In principle, this evolutionarily highly conserved, rapid first-line defense system responds to pathogen-induced injury with the creation of infectious inflammation, and non-pathogen-induced tissue injury with ‘sterile’ tissue inflammation. In this review, evidence has been collected in support of the notion that the transfusion-related acute lung injury induces a ‘sterile’ inflammation in the lung of transfused patients in terms of an acute innate inflammatory disease. The inflammatory response is mediated by the patient's innate immune cells including lung-passing neutrophils and pulmonary endothelial cells, which are equipped with pattern recognition receptors. These receptors are able to sense injury-induced, damage-associated molecular patterns (DAMPs) generated during collection, processing, and storage of blood/blood components. The recognition process leads to activation of these innate cells. A critical role for a protein complex known as the NLRP3 inflammasome has been suggested to be at the center of such a scenario. This complex undergoes an initial ‘priming’ step mediated by 1 class of DAMPs and then an ‘activating’ step mediated by another class of DAMPs to activate interleukin-1beta and interleukin-18. These 2 cytokines then promote, via transactivation, the formation of lung inflammation. PMID:23637644

  13. Resolution of Acute Inflammation In The Lung

    PubMed Central

    Levy, Bruce D.; Serhan, Charles N.

    2015-01-01

    Acute inflammation in the lung is essential to health. So too is its resolution. In response to invading microbes, noxious stimuli or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized pro-resolving mediators, specifically lipoxins, resolvins, protectins and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung. PMID:24313723

  14. Resolution of acute inflammation in the lung.

    PubMed

    Levy, Bruce D; Serhan, Charles N

    2014-01-01

    Acute inflammation in the lung is essential to health. So too is its resolution. In response to invading microbes, noxious stimuli, or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized proresolving mediators, specifically lipoxins, resolvins, protectins, and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung. PMID:24313723

  15. Oxidants in Acute and Chronic Lung Disease

    PubMed Central

    Mannam, Praveen; Srivastava, Anup; Sugunaraj, Jaya Prakash; Lee, Patty J; Sauler, Maor

    2015-01-01

    Oxidants play an important role in homeostatic function, but excessive oxidant generation has an adverse effect on health. The manipulation of Reactive Oxygen Species (ROS) can have a beneficial effect on various lung pathologies. However indiscriminate uses of anti-oxidant strategies have not demonstrated any consistent benefit and may be harmful. Here we propose that nuanced strategies are needed to modulate the oxidant system to obtain a beneficial result in the lung diseases such as Acute Lung Injury (ALI) and Chronic Obstructive Pulmonary Disease (COPD). We identify novel areas of lung oxidant responses that may yield fruitful therapies in the future. PMID:25705575

  16. Animal models of acute lung injury

    PubMed Central

    Matute-Bello, Gustavo; Frevert, Charles W.; Martin, Thomas R.

    2008-01-01

    Acute lung injury in humans is characterized histopathologically by neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Most are based on reproducing in animals known risk factors for ARDS, such as sepsis, lipid embolism secondary to bone fracture, acid aspiration, ischemia-reperfusion of pulmonary or distal vascular beds, and other clinical risks. However, none of these models fully reproduces the features of human lung injury. The goal of this review is to summarize the strengths and weaknesses of existing models of lung injury. We review the specific features of human ARDS that should be modeled in experimental lung injury and then discuss specific characteristics of animal species that may affect the pulmonary host response to noxious stimuli. We emphasize those models of lung injury that are based on reproducing risk factors for human ARDS in animals and discuss the advantages and disadvantages of each model and the extent to which each model reproduces human ARDS. The present review will help guide investigators in the design and interpretation of animal studies of acute lung injury. PMID:18621912

  17. Translational Insights on Lung Transplantation: Learning from Immunology.

    PubMed

    Mohamed, Mohamed Shehata Ali

    2015-09-01

    The introduction of ex vivo lung perfusion (EVLP) in the practice of lung transplantation has allowed the reconditioning of the marginal grafts and their conversion into transplantable grafts. In addition, EVLP can provide a platform for the application of various preventive measures to decrease the incidence of post-transplant complications. While the Toronto team targets the attenuation of the cytokine production within the graft through gene therapy to up-regulate IL-10, other measures could be applied to achieve significant attenuation of the cytokine load of the graft. This manuscript provides a short overview on the importance of the attenuation of the cytokine production within the transplanted lung grafts and some possible strategies to achieve this goal. PMID:26412634

  18. Flow cytometry applications in the study of immunological lung disorders.

    PubMed

    Mortaz, Esmaeil; Gudarzi, Hoda; Tabarsi, Payam; M Adcock, Ian; Masjedi, Mohamad Reza; Jamaati, Hamid Reza; Garssen, Johan; Velayati, Ali Akbar; A Redegeld, Frank

    2015-02-01

    The use of flow cytometry in the clinical laboratory has grown substantially in the past decade. Flow cytometric analysis provides a rapid qualitative and quantitative description of multiple characteristics of individual cells. For example, it is possible to detect the cell size and granularity, aspects of DNA and RNA content and the presence of cell surface and nuclear markers which are used to characterize the phenotype of single cells. Flow cytometry has been used for the immunophenotyping of a variety of specimens including whole blood, bone marrow, serous cavity fluids, (cerebrospinal fluid) CSF, urine and all types of body fluids. The technique has also been applied to human bronchoalveolar lavage (BAL) fluid, peritoneal fluids and blood. In this review, we describe the current status of the application of flow cytometry as a diagnostic tool in various lung diseases. We focus on the analysis of BAL cell composition in chronic obstructive lung disease (COPD), asthma, lung cancer, sarcoidosis, tuberculosis and idiopathic eosinophilic pneumonia (IEP). PMID:25530134

  19. Cytokine mRNA expression in lung tissue from toxic oil syndrome patients: a TH2 immunological mechanism.

    PubMed

    del Pozo, V; de Andrés, B; Gallardo, S; Cárdaba, B; de Arruda-Chaves, E; Cortegano, M I; Jurado, A; Palomino, P; Oliva, H; Aguilera, B; Posada, M; Lahoz, C

    1997-03-14

    In 1981, an epidemic occurred in Spain, toxic oil syndrome (TOS), in people who consumed rapeseed oil denatured with 2% aniline, and it was one of the largest intoxication epidemics ever recorded. In 1989, a similar disease, eosinophilia-myalgia syndrome (EMS) was reported in the USA and was associated with the ingestion of L-tryptophan. The pathologic findings in TOS showed primary endothelial injury, with cell proliferation and perivascular inflammatory infiltrates. Immunologic mechanisms have presumably been operative in the pathogenesis and perpetuation of TOS. Our previous findings pointed to a T-cell activation during acute phase of the disease. In order to analyze which T-cell subset is involved on TOS, we have developed an mRNA extraction procedure from paraffin-embedded lung tissues in patients with pulmonary involvement. We analyzed mRNA expression from different cytokines (IL-1, IL-2, IL-4, IL-5, IFN-gamma, GM-CSF) and CD25 (interleukin 2 receptor) and CD23 (low affinity IgE receptor), using RT-PCR technique. In lung tissues from these patients a T-cell activation was observed. We found a significant increase in Th1 (P = 0.006) and Th2 (P = 0.003) cytokine profile in TOS patients with respect to controls. The increment in TH2 response with respect to TH1 is significant (P = 0.03) in TOS lung specimens. Non-significant differences were obtained in other cytokines and receptors studied as IL-1, CD25, CD23 and GM-CSF. Data presented in this paper are the first clear evidence that an immunological mechanism is directly implicated in this illness. PMID:9074654

  20. Modulation of acute lung injury by integrins.

    PubMed

    Sheppard, Dean

    2012-07-01

    Acute lung injury is a common disorder with a high mortality rate, but previous efforts to develop drugs to treat this disorder have been unsuccessful. In an effort to develop more effective treatments, we have been studying the molecular pathways that regulate the dysfunction of alveolar epithelial cells and endothelial cells that serve as a final common pathway leading to alveolar flooding. Using integrin subunit knockout mice and antibodies we developed by immunizing these mice, we have found important and distinct roles for the αvβ6 integrin on epithelial cells and the αvβ5 integrin on endothelial cells in mediating increases in alveolar permeability in multiple models of acute lung injury. We have also found therapeutic effects of αvβ5 inhibition in two models of septic shock even when the antibody was administered to animals that were obviously ill. These results identify αvβ6 and αvβ5 as promising therapeutic targets for the treatment of acute lung injury and septic shock. PMID:22802286

  1. Human models of acute lung injury

    PubMed Central

    Proudfoot, Alastair G.; McAuley, Danny F.; Griffiths, Mark J. D.; Hind, Matthew

    2011-01-01

    Acute lung injury (ALI) is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome. PMID:21357760

  2. A prospective study of acute idiopathic neuropathy. III. Immunological studies.

    PubMed Central

    Winer, J B; Gray, I A; Gregson, N A; Hughes, R A; Leibowitz, S; Shepherd, P; Taylor, W A; Yewdall, V

    1988-01-01

    The immune responses of 100 patients who presented with an acute idiopathic neuropathy were compared with those of age and sex matched controls. Blood lymphocytes and their subsets were counted with a fluorescent activated cell sorter. CD8+ (putative suppressor) lymphocytes were significantly reduced in the first week of the disease but total lymphocytes, total T and CD4+ (putative helper) cells were not altered. This reduction depended on the nature of the preceding infection. Serum complement C3 and C4 concentrations remained normal and immune complexes were rarely detected with a C1q binding assay. Complement-fixing antibodies to human peripheral nerve antigens were discovered in the serum of 7% of patients but only 1% of controls. Complement-fixing antibodies to galactocerebroside were not discovered in any sera. Enzyme-linked immunoassays detected increased antibody responses to galactocerebroside but none at all to human P2 myelin protein in the patient sera. Forty microliter of serum from five patients injected into the sciatic nerves of rats did not induce significantly more demyelination than the serum from control patients. It is concluded that auto-immune responses can only be detected by these techniques in a small minority of patients with acute idiopathic neuropathy. PMID:2969956

  3. Immunological Aspects of Acute and Recurrent Herpes Simplex Keratitis

    PubMed Central

    Hus, Iwona

    2014-01-01

    Herpes simplex keratitis (HSK) belongs to the major causes of visual morbidity worldwide and available methods of treatment remain unsatisfactory. Primary infection occurs usually early in life and is often asymptomatic. Chronic visual impairment and visual loss are caused by corneal scaring, thinning, and vascularization connected with recurrent HSV infections. The pathogenesis of herpetic keratitis is complex and is still not fully understood. According to the current knowledge, corneal scarring and vascularization are the result of chronic inflammatory reaction against HSV antigens. In this review we discuss the role of innate and adaptive immunities in acute and recurrent HSV ocular infection and present the potential future targets for novel therapeutical options based on immune interventions. PMID:25276842

  4. Clinical, histopathologic & immunologic features of cutaneous lesions in acute meningococcaemia.

    PubMed

    Ramesh, V; Mukherjee, A; Chandra, M; Sehgal, S K; Saxena, U; Jain, A K; Wadhwa, A

    1990-01-01

    Fifty children with culture proven acute meningococcaemia were studied during the winter outbreak of the disease in 1986-87. Purpuric lesions were seen in 60 per cent, erythematous papules in 32 per cent, faint pink macules in 28 per cent, conjunctival petechiae in 10 per cent and herpes labialis in 20 per cent. Histopathology of skin lesions showed that the primary damage was to the dermal vessels, the extent of damage depending on the type of skin involvement. Diplococci in Gram's stained sections were seen frequently in purpuric as compared to the other skin lesions. They were located in degenerating neutrophils, endothelial cells, fibrin clots or freely in the vascular lumen. Electron microscopic study showed vascular changes accompanied by a perivascular phagocytic response. Both light and electronmicroscopy indicated the involvement of the coagulative mechanism in the pathogenesis of meningococcaemia. However, clinical parameters of clotting were often within normal limits. In the case of a child (who died eventually), a low platelet count and prolonged coagulation indices were observed. Sera from some of the children were tested for the presence of antibodies against meningococci by indirect immunofluorescence. Antibodies were detected in the sera and they may have a role in regulating the severity and course of the illness. The significance of immunoglobulin deposits in the skin lesions is not clear. PMID:2111800

  5. Treatment of acute silicoproteinosis by whole-lung lavage.

    PubMed

    Stafford, Marshall; Cappa, Anthony; Weyant, Michael; Lara, Abigail; Ellis, James; Weitzel, Nathaen S; Puskas, Ferenc

    2013-06-01

    Acute silicoproteinosis is a rare disease that occurs following a heavy inhalational exposure to silica dusts. Clinically, it resembles pulmonary alveolar proteinosis (PAP); silica exposure is thought to be a cause of secondary PAP. We describe a patient with biopsy-confirmed acute silicoproteinosis whose course was complicated by acute hypoxemic respiratory failure requiring mechanical ventilation. Without clinical improvement despite antibiotic and steroid treatment, the patient was scheduled for whole-lung lavage under general anesthesia. Anesthetic challenges included double-lumen tube placement and single-lung ventilation in a hypoxic patient, facilitating lung lavage, and protecting the contralateral lung from catastrophic spillage. PMID:23632425

  6. Transfusion-related acute lung injury (TRALI).

    PubMed

    Roberts, George H

    2004-01-01

    Transfusion is an inevitable event in the life of many individuals. Transfusion medicine personnel attempt to provide blood products that will result in a safe and harmless transfusion. However, this is not always possible since no laboratory test gives totally accurate and reliable results all the time and testing in routine transfusion services is devoted primarily to the identification of red blood cell problems. Thus, when patients are transfused, several possible adverse effects may occur in the transfused patient even though quality testing indicates no potential problem. These adverse events include infectious complications, hemolytic reactions, anaphylaxis, urticaria, circulatory overload, transfusion-associated graft-versus-host disease, chills and fever, immunomodulation, and transfusion-related acute lung injury (TRALI). PMID:15314887

  7. [A specific rosette formation method in assessing the immunological status of acute leukemia patients].

    PubMed

    Moroz, I A

    1985-01-01

    The paper deals with the evaluation of immunologic vigor in 88 patients suffering acute lymphoblastic leukemia. It involved a modified test of specific rosette formation of blood-circulating lymphocytes and those of the bone marrow with erythrocytes bearing leukemia cell extracts. The highest levels of rosette-forming lymphocytes were registered in the acute period prior to treatment and in recurrence. The said levels decreased gradually following chemoimmunotherapy, falling to nil in complete remission. Patients in whom the treatment had failed revealed no changes in lymphocyte response. The control group (healthy subjects and cases of nonmalignant hematologic pathology) showed levels of rosette-forming lymphocytes similar to those in acute lymphoblastic leukemia patients in remission. PMID:3861026

  8. [Transfusion-related acute lung injury].

    PubMed

    Tank, S; Sputtek, A; Kiefmann, R

    2013-04-01

    Transfusion-related acute lung injury (TRALI) developed into the leading cause of transfusion-related morbidity and mortality after the first description by Popovsky et al. approximately three decades ago. It was the most frequent reason for transfusion-related fatalities worldwide before implementation of risk minimization strategies by donor selection. Plasma-rich blood products, such as fresh frozen plasma and apheresis platelets seem to be the leading triggers of TRALI. Hypoxemia and development of pulmonary edema within 6 h of transfusion are the diagnostic criteria for TRALI. The differentiation between cardiac failure and other transfusion-related lung injuries, such astransfusion-associated circulatory overload ( TACO) is difficult and causal treatment is not available. Therapy is based on supportive measures, such as oxygen insufflationor mechanical ventilation. The exactly pathogenesis is still unknown but the most propagated hypothesis is the two-event-model. Neutrophils are primed by the underlying condition, e.g. sepsis or trauma during the first event and these primed neutrophils are activated by transfused leukoagglutinating antibodies (immunogen) or bioreactive mediators (non-immunogen) during the second-event. Transfusion of leukoagglutinating antibodies from female donors with one or more previous pregnancies is the most frequent reason. No more TRALI fatalities were reported after implementation of the donor selection in Germany in 2009. PMID:23558721

  9. Antiradiation Vaccine: Immunological neutralization of Radiation Toxins at Acute Radiation Syndromes.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Slava

    . Material and Methods: The SRD molecules were isolated from Lymphatic Systems of animals that were irradiated with high doses of irradiation and had a clinical and laboratory picture of the Cerebral Acute Radia-tion Syndrome, Cardiovascular Acute Radiation Syndrome, Gastrointestinal Acute Radiation Syndrome, and Hematological Acute Radiation Syndrome. Our classification of radiation tox-ins includes 4 major groups: 1.SRD-1, Cerebrovascular neurotoxic Radiation Toxins (CvARS); 2.SRD-2, Cardiovascular Radiation Toxins(CrARS); 3.SRD-3,Gastrointestinal neurotoxic Ra-diation Toxins (GiARS); 4.SRD-4, Hematopietic Radiation Toxins (HpARS). Radiation tox-ins possess both toxic and immunological properties. But mechanisms of immune-toxicity by which radiation toxins stimulate development of the ARS are poorly understood. We have studied lethal toxicity of radiation toxins and an ability of specific antibodies to neutralize toxic activity of radiation toxins by specific antibodies. Results: The Blocking Antiradiation Antibodies induce an immunologically specific effect and inhibiting effects on radiation induced neuro-toxicity, vascular-toxicity, gastrointestinal toxcity, hematopoietic toxicity. Antiradiation Antibodies prevent the radiation induced cytolysis of selected groups of cells that are sensitive to radiation. The Blocking Antiradiation Antibodies are immunologically specific and can be produced by immunization with the different radiation toxins isolated from irradiated mam-mals. We propose that Specific Antiradiation Antibodies targeted against the radiation induced Toxins. Specific Antiradiation Antibodies neutralize toxic properties of radiation toxins. Anti-radiation Antibodies in different phases of the Acute Radiation Syndromes can compete with cytotoxic lymphocytes and prevent cytolysis mediated by cytotoxic lymphocytes. Conclusions: Immunological inhibition of cytotoxic and neurotoxic properties of Specific Radiation Toxins are significant factors for improving

  10. Antiradiation Vaccine: Immunological neutralization of Radiation Toxins at Acute Radiation Syndromes.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Slava

    . Material and Methods: The SRD molecules were isolated from Lymphatic Systems of animals that were irradiated with high doses of irradiation and had a clinical and laboratory picture of the Cerebral Acute Radia-tion Syndrome, Cardiovascular Acute Radiation Syndrome, Gastrointestinal Acute Radiation Syndrome, and Hematological Acute Radiation Syndrome. Our classification of radiation tox-ins includes 4 major groups: 1.SRD-1, Cerebrovascular neurotoxic Radiation Toxins (CvARS); 2.SRD-2, Cardiovascular Radiation Toxins(CrARS); 3.SRD-3,Gastrointestinal neurotoxic Ra-diation Toxins (GiARS); 4.SRD-4, Hematopietic Radiation Toxins (HpARS). Radiation tox-ins possess both toxic and immunological properties. But mechanisms of immune-toxicity by which radiation toxins stimulate development of the ARS are poorly understood. We have studied lethal toxicity of radiation toxins and an ability of specific antibodies to neutralize toxic activity of radiation toxins by specific antibodies. Results: The Blocking Antiradiation Antibodies induce an immunologically specific effect and inhibiting effects on radiation induced neuro-toxicity, vascular-toxicity, gastrointestinal toxcity, hematopoietic toxicity. Antiradiation Antibodies prevent the radiation induced cytolysis of selected groups of cells that are sensitive to radiation. The Blocking Antiradiation Antibodies are immunologically specific and can be produced by immunization with the different radiation toxins isolated from irradiated mam-mals. We propose that Specific Antiradiation Antibodies targeted against the radiation induced Toxins. Specific Antiradiation Antibodies neutralize toxic properties of radiation toxins. Anti-radiation Antibodies in different phases of the Acute Radiation Syndromes can compete with cytotoxic lymphocytes and prevent cytolysis mediated by cytotoxic lymphocytes. Conclusions: Immunological inhibition of cytotoxic and neurotoxic properties of Specific Radiation Toxins are significant factors for improving

  11. Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination.

    PubMed

    Hansen, Gaute Lund; Gaudernack, Gustav; Brunsvig, Paal Fredrik; Cvancarova, Milada; Kyte, Jon Amund

    2015-12-01

    We have previously reported two trials in non-small cell lung cancer (NSCLC) evaluating vaccine therapy with the telomerase peptide GV1001. The studies demonstrated considerable differences in survival among immune responders, highlighting that an immune response is not necessarily beneficial. In the present study, we conducted long-term clinical follow-up and investigated immunological factors hypothesized to influence clinical efficacy. Peripheral blood mononuclear cells from 33 NSCLC trial patients and 15 healthy donors were analyzed by flow cytometry for T regulatory cells (Tregs, CD4(+)CD25(+)CD127(low/-)FOXP3(+)) and two types of myeloid-derived suppressor cells (MDSCs, HLA-DR (low) CD14 (+) or Lin (-/lo) HLA-DR (-) CD33 (+) CD11b (+)). T cell cultures were analyzed for 17 cytokines. The results demonstrated that immune responders had increased overall survival (OS, p < 0.001) and progression-free survival (p = 0.003), compared to subjects without immunological response. The mean OS advantage was 54 versus 13 months. Six patients were still alive at the last clinical update, all belonging to the immune responders. No serious toxicity had developed (maximum observation 13 years). Most patients developed a polyfunctional cytokine profile, with high IFNγ/IL-4 and IFNγ/IL-10 ratios. Low Treg levels were associated with improved OS (p = 0.037) and a favorable cytokine profile, including higher IFNγ/IL-10 ratios. High CD33(+) MDSC levels were associated with poorer immune response rate (p = 0.005). The levels of CD14(+) MDSC were significantly higher in patients than in healthy controls (p = 0.012). We conclude that a randomized GV1001 trial in NSCLC is warranted. The findings suggest that Tregs and MDSCs are associated with a tolerogenic cytokine milieu and impaired clinical efficacy of vaccine responses. PMID:26498005

  12. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection.

    PubMed

    Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E; Padera, Robert F; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D'Agostino, Emmanuel; Goldberg, Hilary J; Perrella, Mark A; Forteza, Rosanna Malbran; Rosas, Ivan O; Visner, Gary; El-Chemaly, Souheil

    2015-11-01

    Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

  13. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

    PubMed Central

    Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E.; Padera, Robert F.; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D’Agostino, Emmanuel; Goldberg, Hilary J.; Perrella, Mark A.; Forteza, Rosanna Malbran; Rosas, Ivan O.; Visner, Gary; El-Chemaly, Souheil

    2015-01-01

    Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

  14. Pathophysiology of pulmonary hypertension in acute lung injury

    PubMed Central

    Price, Laura C.; McAuley, Danny F.; Marino, Philip S.; Finney, Simon J.; Griffiths, Mark J.

    2012-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome are characterized by protein rich alveolar edema, reduced lung compliance, and acute severe hypoxemia. A degree of pulmonary hypertension (PH) is also characteristic, higher levels of which are associated with increased morbidity and mortality. The increase in right ventricular (RV) afterload causes RV dysfunction and failure in some patients, with associated adverse effects on oxygen delivery. Although the introduction of lung protective ventilation strategies has probably reduced the severity of PH in ALI, a recent invasive hemodynamic analysis suggests that even in the modern era, its presence remains clinically important. We therefore sought to summarize current knowledge of the pathophysiology of PH in ALI. PMID:22246001

  15. Mechanical ventilation of patients with acute lung injury.

    PubMed

    Sessler, C N

    1998-10-01

    Ventilatory management of patients with acute lung injury (ALI), particularly its most severe subset, acute respiratory distress syndrome (ARDS), is complex. Newer lung protective strategies emphasize measures to enhance alveolar recruitment and avoid alveolar overdistention, thus minimizing the risk of ventilator-induced lung injury (VILI). Key components of such strategies include the use of smaller-than-conventional tidal volumes which maintain peak transpulmonary pressure below the pressure associated with overdistention, and titration of positive end-expiratory pressure to promote maximal alveolar recruitment. Novel techniques, including prone positioning, inverse ratio ventilation, tracheal gas insufflation, and high frequency ventilation, are considerations in severe ARDS. No single approach is best for all patients; adjustment of ventilatory parameters to individual characteristics, such as lung mechanics and gas exchange, is required. PMID:9891634

  16. Pancreatitis-induced acute lung injury. An ARDS model.

    PubMed Central

    Guice, K S; Oldham, K T; Johnson, K J; Kunkel, R G; Morganroth, M L; Ward, P A

    1988-01-01

    Cerulein-induced acute pancreatitis in rats is associated with acute lung injury characterized by increased pulmonary microvascular permeability, increased wet lung weights, and histologic features of alveolar capillary endothelial cell and pulmonary parenchymal injury. The alveolar capillary permeability index is increased 1.8-fold after a 3-hour injury (0.30 to 0.54, p less than 0.05). Gravimetric analysis shows a similar 1.5-fold increase in wet lung weights at 3 hours (0.35% vs. 0.51% of total body weight, p less than 0.05). Histologic features assessed by quantitative morphometric analysis include significant intra-alveolar hemorrhage (0.57 +/- 0.08 vs. 0.12 +/- 0.02 RBC/alveolus at 6 hours, p less than 0.001); endothelial cell disruption (28.11% vs. 4.3%, p less than 0.001); and marked, early neutrophil infiltration (7.45 +/- 0.53 vs. 0.83 +/- 0.18 PMN/hpf at 3 hours, p less than 0.001). The cerulein peptide itself, a cholecystokinin (CCK) analog, is naturally occurring and is not toxic and in several in vitro settings including exposure to pulmonary artery endothelial cells, Type II epithelial cells, and an ex vivo perfused lung preparation. The occurrence of this ARDS-like acute lung injury with acute pancreatitis provides an excellent experimental model to investigate mechanisms and mediators involved in the pathogenesis of ARDS. Images Fig. 1. PMID:3389946

  17. Pancreatitis-induced acute lung injury. An ARDS model.

    PubMed

    Guice, K S; Oldham, K T; Johnson, K J; Kunkel, R G; Morganroth, M L; Ward, P A

    1988-07-01

    Cerulein-induced acute pancreatitis in rats is associated with acute lung injury characterized by increased pulmonary microvascular permeability, increased wet lung weights, and histologic features of alveolar capillary endothelial cell and pulmonary parenchymal injury. The alveolar capillary permeability index is increased 1.8-fold after a 3-hour injury (0.30 to 0.54, p less than 0.05). Gravimetric analysis shows a similar 1.5-fold increase in wet lung weights at 3 hours (0.35% vs. 0.51% of total body weight, p less than 0.05). Histologic features assessed by quantitative morphometric analysis include significant intra-alveolar hemorrhage (0.57 +/- 0.08 vs. 0.12 +/- 0.02 RBC/alveolus at 6 hours, p less than 0.001); endothelial cell disruption (28.11% vs. 4.3%, p less than 0.001); and marked, early neutrophil infiltration (7.45 +/- 0.53 vs. 0.83 +/- 0.18 PMN/hpf at 3 hours, p less than 0.001). The cerulein peptide itself, a cholecystokinin (CCK) analog, is naturally occurring and is not toxic and in several in vitro settings including exposure to pulmonary artery endothelial cells, Type II epithelial cells, and an ex vivo perfused lung preparation. The occurrence of this ARDS-like acute lung injury with acute pancreatitis provides an excellent experimental model to investigate mechanisms and mediators involved in the pathogenesis of ARDS. PMID:3389946

  18. Plasmacytoid Dendritic Cells Control Lung Inflammation and Monocyte Recruitment in Indirect Acute Lung Injury in Mice

    PubMed Central

    Venet, Fabienne; Huang, Xin; Chung, Chun-Shiang; Chen, Yaping; Ayala, Alfred

    2010-01-01

    Indirect acute lung injury (ALI, not caused by a direct insult to the lung) represents the first organ dysfunction in trauma patients, with nonpulmonary sepsis being the most common cause of indirect ALI. Dendritic cells (DCs) are thought to participate in a number of inflammatory lung diseases; however, their role in indirect ALI is currently not established. Using a clinically relevant model of indirect ALI induced in mice by hemorrhagic shock followed 24 hours later by polymicrobial septic challenge, we report that mature DC numbers were markedly increased in the lung during indirect ALI. DC depletion induced a significant increase in indirect ALI severity, which was associated with enhanced lung and plasma proinflammatory cytokine concentration and recruitment of proinflammatory CD115+ monocytes in response to increased lung monocyte chemotactic protein-1 production. Among the different DC subpopulations, plasmacytoid DCs, which were induced and activated in the lung during indirect ALI, were responsible for this effect because their specific depletion reproduced the observations made in DC-depleted mice. As the recruitment of monocytes to the lung plays a central deleterious role in the pathophysiology of indirect ALI, our data therefore position plasmacytoid DCs as important regulators of acute lung inflammation. PMID:20042672

  19. Roles of dopamine receptors in mediating acute modulation of immunological responses in Macrobrachium rosenbergii.

    PubMed

    Chang, Zhong-Wen; Ke, Zhi-Han; Chang, Chin-Chyuan

    2016-02-01

    Dopamine (DA) was found to influence the immunological responses and resistance to pathogen infection in invertebrates. To clarify the possible modulation of DA through dopamine receptors (DAR) against acute environmental stress, the levels of DA, glucose and lactate in the haemolymph of Macrobrachium rosenbergii under hypo- and hyperthermal stresses were measured. The changes in immune parameters such as total haemocyte count (THC), differential haemocyte count (DHC), phenoloxidase (PO) activity, respiratory bursts (RBs), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and phagocytic activity (PA) were evaluated in prawns which received DAR antagonists (SCH23390, SCH, D1 antagonist; domperidone, DOM, D2 antagonist; chlorpromazine, CH, D1+2 antagonist) followed by hypo- (15 °C) and hyperthermal (34 °C) stresses. In addition, pharmacological analysis of the effect DA modulation was studied in haemocytes incubated with DA and DAR antagonists. The results revealed a significant increase in haemolymph DA accompanied with upregulated levels of glucose and lactate in prawns exposed to both hypo- and hyperthermal stresses in 2 h. In addition, a significant decrease in RBs per haemocyte was noted in prawns which received DAR antagonists when they exposed to hyperthermal stress for 30 min. In in vitro test, antagonism on RBs, SOD and GPx activity of haemocytes were further evidenced through D1, D1, D1+D2 DARs, respectively, in the meantime, no significant difference in PO activity and PA was observed among the treatment groups. These results suggest that the upregulation of DA, glucose and lactate in haemolymph might be the response to acute thermal stress for the demand of energy, and the DAR occupied by its antagonistic action impart no effect on immunological responses except RBs in vivo even though the modulation mediated through D1 DAR was further evidenced in RBs, SOD and GPx activities in vitro. It is therefore concluded that thermal

  20. [Effect of acetylsalicylic acid on immunologically induced morphologic changes after experimental lung transplantation (light and electron microscopic study)].

    PubMed

    Hoyer, J; Garbe, L; Sicardi, F; Noirclerc, M

    1976-01-01

    In 3 comparing series the behavior of platelets after experimental lung transplantation was examined in 33 dogs. After allogenic transplantations (21 animals) the ultrastructural findings were pathologic changes of the platelets, such as hyperaggregability with irreversible aggregation prevailing, as well as capillary wall alterations. X-rays showed considerable reduction of functioning parenchyma. Since these findings were absent in animals which underwent merely pulmonary re-implantation (4 animals) and can be considered a controll group, the authors conclude that these alterations are caused by mainly immunologic reactions. Acetylsalicylic acid given to animals with grafted lungs significantly inhibited is specific and certainly immuneinduced pathologic development. Absolutely necessary, therefore, appears the application of such aggregation inhibitor as additional treatment in lung transplantations. PMID:793217

  1. Diverse macrophage populations mediate acute lung inflammation and resolution

    PubMed Central

    King, Landon S.; D'Alessio, Franco R.

    2014-01-01

    Acute respiratory distress syndrome (ARDS) is a devastating disease with distinct pathological stages. Fundamental to ARDS is the acute onset of lung inflammation as a part of the body's immune response to a variety of local and systemic stimuli. In patients surviving the inflammatory and subsequent fibroproliferative stages, transition from injury to resolution and recovery is an active process dependent on a series of highly coordinated events regulated by the immune system. Experimental animal models of acute lung injury (ALI) reproduce key components of the injury and resolution phases of human ARDS and provide a methodology to explore mechanisms and potential new therapies. Macrophages are essential to innate immunity and host defense, playing a featured role in the lung and alveolar space. Key aspects of their biological response, including differentiation, phenotype, function, and cellular interactions, are determined in large part by the presence, severity, and chronicity of local inflammation. Studies support the importance of macrophages to initiate and maintain the inflammatory response, as well as a determinant of resolution of lung inflammation and repair. We will discuss distinct roles for lung macrophages during early inflammatory and late resolution phases of ARDS using experimental animal models. In addition, each section will highlight human studies that relate to the diverse role of macrophages in initiation and resolution of ALI and ARDS. PMID:24508730

  2. Racial and Ethnic Disparities in Mortality from Acute Lung Injury

    PubMed Central

    Erickson, Sara E.; Shlipak, Michael G.; Martin, Greg S.; Wheeler, Arthur P.; Ancukiewicz, Marek; Matthay, Michael A.; Eisner, Mark D.

    2009-01-01

    Objective: Little is known about the influence of race and ethnicity on mortality from acute lung injury. We sought to determine whether black race or Hispanic ethnicity are independently associated with mortality among patients with acute lung injury. Design: Retrospective cohort study of patients enrolled in the Acute Respiratory Distress Syndrome (ARDS) Network randomized controlled trials. Setting: Adult intensive care units participating in the ARDS Network trials. Patients: 2362 mechanically ventilated patients (1,715 white, 449 black and 198 Hispanic) with acute lung injury. Measurements and Main Results: The primary outcome was 60-day mortality. A secondary outcome was number of ventilator-free days. Crude mortality was 33% for both blacks and Hispanics compared with 27% for whites (p=0.02). After adjusting for demographic and clinical covariates, the association between race/ethnicity and mortality persisted (OR = 1.42; 95% CI 1.10-1.84 for blacks; OR=1.94; 95% CI, 1.36-2.77 for Hispanics; OR=1 for whites, reference). After adjustment for severity of illness (Acute Physiology Score), black race was no longer significantly associated with mortality (OR =1.25; 95% CI, 0.95-1.66), whereas the association with Hispanic ethnicity persisted (OR=2.00; 95% CI, 1.37-2.90). Hispanics had significantly fewer ventilator-free days compared with whites after adjustment for demographic and clinical covariates (mean difference in days = -2.3; 95% CI -3.9 to -0.7). Conclusions: Black and Hispanic patients with acute lung injury have a significantly higher risk of death compared to white patients. This increased risk appeared to be mediated by increased severity of illness at presentation for blacks, but was unexplained among Hispanics. PMID:19050621

  3. Effects of acute hypercapnia with and without acidosis on lung inflammation and apoptosis in experimental acute lung injury.

    PubMed

    Nardelli, L M; Rzezinski, A; Silva, J D; Maron-Gutierrez, T; Ornellas, D S; Henriques, I; Capelozzi, V L; Teodoro, W; Morales, M M; Silva, P L; Pelosi, P; Garcia, C S N B; Rocco, P R M

    2015-01-01

    We investigated the effects of acute hypercapnic acidosis and buffered hypercapnia on lung inflammation and apoptosis in experimental acute lung injury (ALI). Twenty-four hours after paraquat injection, 28 Wistar rats were randomized into four groups (n=7/group): (1) normocapnia (NC, PaCO2=35-45 mmHg), ventilated with 0.03%CO2+21%O2+balancedN2; (2) hypercapnic acidosis (HC, PaCO2=60-70 mmHg), ventilated with 5%CO2+21%O2+balancedN2; and (3) buffered hypercapnic acidosis (BHC), ventilated with 5%CO2+21%O2+balancedN2 and treated with sodium bicarbonate (8.4%). The remaining seven animals were not mechanically ventilated (NV). The mRNA expression of interleukin (IL)-6 (p=0.003), IL-1β (p<0.001), and type III procollagen (PCIII) (p=0.001) in lung tissue was more reduced in the HC group in comparison with NC, with no significant differences between HC and BHC. Lung and kidney cell apoptosis was reduced in HC and BHC in comparison with NC and NV. In conclusion, in this experimental ALI model, hypercapnia, regardless of acidosis, reduced lung inflammation and lung and kidney cell apoptosis. PMID:25246186

  4. Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury

    PubMed Central

    Lee, Sang-Min; McLaughlin, Joseph N.; Frederick, Daniel R.; Zhu, Lin; Thambiayya, Kalidasan; Wasserloos, Karla J.; Kaminski, Iris; Pearce, Linda L.; Peterson, Jim; Li, Jin; Latoche, Joseph D.; Peck Palmer, Octavia M.; Stolz, Donna Beer; Fattman, Cheryl L.; Alcorn, John F.; Oury, Tim D.; Angus, Derek C.; Pitt, Bruce R.

    2013-01-01

    Hypozincemia, with hepatic zinc accumulation at the expense of other organs, occurs in infection, inflammation, and aseptic lung injury. Mechanisms underlying zinc partitioning or its impact on extrahepatic organs are unclear. Here we show that the major zinc-binding protein, metallothionein (MT), is critical for zinc transmigration from lung to liver during hyperoxia and preservation of intrapulmonary zinc during hyperoxia is associated with an injury-resistant phenotype in MT-null mice. Particularly, lung-to-liver zinc ratios decreased in wild-type (WT) and increased significantly in MT-null mice breathing 95% oxygen for 72 h. Compared with female adult WT mice, MT-null mice were significantly protected against hyperoxic lung injury indicated by reduced inflammation and interstitial edema, fewer necrotic changes to distal airway epithelium, and sustained lung function at 72 h hyperoxia. Lungs of MT-null mice showed decreased levels of immunoreactive LC3, an autophagy marker, compared with WT mice. Analysis of superoxide dismutase (SOD) activity in the lungs revealed similar levels of manganese-SOD activity between strains under normoxia and hyperoxia. Lung extracellular SOD activity decreased significantly in both strains at 72 h of hyperoxia, although there was no difference between strains. Copper-zinc-SOD activity was ∼4× higher under normoxic conditions in MT-null compared with WT mice but was not affected in either group by hyperoxia. Collectively the data suggest that genetic deletion of MT-I/II in mice is associated with compensatory increase in copper-zinc-SOD activity, prevention of hyperoxia-induced zinc transmigration from lung to liver, and hyperoxia-resistant phenotype strongly associated with differences in zinc homeostasis during hyperoxic acute lung injury. PMID:23275622

  5. Dasatinib Reduces Lung Inflammation and Fibrosis in Acute Experimental Silicosis

    PubMed Central

    Cruz, Fernanda Ferreira; Horta, Lucas Felipe Bastos; Maia, Lígia de Albuquerque; Lopes-Pacheco, Miquéias; da Silva, André Benedito; Morales, Marcelo Marco; Gonçalves-de-Albuquerque, Cassiano Felippe; Takiya, Christina Maeda; de Castro-Faria-Neto, Hugo Caire; Rocco, Patricia Rieken Macedo

    2016-01-01

    Silicosis is an occupational lung disease with no effective treatment. We hypothesized that dasatinib, a tyrosine kinase inhibitor, might exhibit therapeutic efficacy in silica-induced pulmonary fibrosis. Silicosis was induced in C57BL/6 mice by a single intratracheal administration of silica particles, whereas the control group received saline. After 14 days, when the disease was already established, animals were randomly assigned to receive DMSO or dasatinib (1 mg/kg) by oral gavage, twice daily, for 14 days. On day 28, lung morphofunction, inflammation, and remodeling were investigated. RAW 264.7 cells (a macrophage cell line) were incubated with silica particles, followed by treatment or not with dasatinib, and evaluated for macrophage polarization. On day 28, dasatinib improved lung mechanics, increased M2 macrophage counts in lung parenchyma and granuloma, and was associated with reduction of fraction area of granuloma, fraction area of collapsed alveoli, protein levels of tumor necrosis factor-α, interleukin-1β, transforming growth factor-β, and reduced neutrophils, M1 macrophages, and collagen fiber content in lung tissue and granuloma in silicotic animals. Additionally, dasatinib reduced expression of iNOS and increased expression of arginase and metalloproteinase-9 in silicotic macrophages. Dasatinib was effective at inducing macrophage polarization toward the M2 phenotype and reducing lung inflammation and fibrosis, thus improving lung mechanics in a murine model of acute silicosis. PMID:26789403

  6. Crocin attenuates lipopolysacchride-induced acute lung injury in mice

    PubMed Central

    Wang, Jian; Kuai, Jianke; Luo, Zhonghua; Wang, Wuping; Wang, Lei; Ke, Changkang; Li, Xiaofei; Ni, Yunfeng

    2015-01-01

    Crocin, a representative of carotenoid compounds, exerts a spectrum of activities including radical scavenger, anti-microbial and anti-inflammatory properties. To investigate the protective effect of crocin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg). The mice received intragastric injection of crocin (50 mg/kg) 1 h before LPS administration. Pulmonary histological changes were evaluated by hematoxylineosin stain and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and nitric oxide (NO), and myeloperoxidase (MPO) activity were measured by enzymelinked immunosorbent assay. Expression of inducible nitric oxide synthase (iNOS) in lung tissues was determined by Western blot analysis. Crocin pretreatment significantly alleviated the severity of lung injury and inhibited the production of TNF-α and IL-1β in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by crocin pretreatment. Crocin pretreatment also reduced the concentrations of NO in lung tissues. Furthermore, the expression of iNOS was significantly suppressed by crocin pretreatment. Croncin potently protected against LPS-induced ALI and the protective effects of crocin may attribute partly to the suppression of iNOS expression. PMID:26191176

  7. Dasatinib Reduces Lung Inflammation and Fibrosis in Acute Experimental Silicosis.

    PubMed

    Cruz, Fernanda Ferreira; Horta, Lucas Felipe Bastos; Maia, Lígia de Albuquerque; Lopes-Pacheco, Miquéias; da Silva, André Benedito; Morales, Marcelo Marco; Gonçalves-de-Albuquerque, Cassiano Felippe; Takiya, Christina Maeda; de Castro-Faria-Neto, Hugo Caire; Rocco, Patricia Rieken Macedo

    2016-01-01

    Silicosis is an occupational lung disease with no effective treatment. We hypothesized that dasatinib, a tyrosine kinase inhibitor, might exhibit therapeutic efficacy in silica-induced pulmonary fibrosis. Silicosis was induced in C57BL/6 mice by a single intratracheal administration of silica particles, whereas the control group received saline. After 14 days, when the disease was already established, animals were randomly assigned to receive DMSO or dasatinib (1 mg/kg) by oral gavage, twice daily, for 14 days. On day 28, lung morphofunction, inflammation, and remodeling were investigated. RAW 264.7 cells (a macrophage cell line) were incubated with silica particles, followed by treatment or not with dasatinib, and evaluated for macrophage polarization. On day 28, dasatinib improved lung mechanics, increased M2 macrophage counts in lung parenchyma and granuloma, and was associated with reduction of fraction area of granuloma, fraction area of collapsed alveoli, protein levels of tumor necrosis factor-α, interleukin-1β, transforming growth factor-β, and reduced neutrophils, M1 macrophages, and collagen fiber content in lung tissue and granuloma in silicotic animals. Additionally, dasatinib reduced expression of iNOS and increased expression of arginase and metalloproteinase-9 in silicotic macrophages. Dasatinib was effective at inducing macrophage polarization toward the M2 phenotype and reducing lung inflammation and fibrosis, thus improving lung mechanics in a murine model of acute silicosis. PMID:26789403

  8. MicroRNAs: Novel regulatory molecules in acute lung injury/acute respiratory distress syndrome

    PubMed Central

    CAO, YONGMEI; LYU, YI; TANG, JIAHUA; LI, YINGCHUAN

    2016-01-01

    Acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS) are common and complex inflammatory lung diseases. MicroRNAs (miRNAs), a type of non-coding RNA molecule that regulate gene expression at the post-transcriptional level, have emerged as a novel class of gene regulators, which have critical roles in a wide range of human disorders and diseases, including ALI. Certain types of miRNAs are abnormally expressed in response to lung injury. miRNAs can regulate inflammation pathways by targeting specific molecules and modulate immune response in the process of lung injury and repair. The regulation of miRNA can relieve injury response and promote the recovery of ALI/ARDS. Therefore, miRNAs may serve as novel therapeutic targets in ALI/ARDS. PMID:27123242

  9. Transfusion-Related Acute Lung Injured (TRALI): Current Concepts

    PubMed Central

    Álvarez, P; Carrasco, R; Romero-Dapueto, C; Castillo, R.L

    2015-01-01

    Transfusion-related acute lung injury (TRALI) is a life-threatening intervention that develops within 6 hours of transfusion of one or more units of blood, and is an important cause of morbidity and mortality resulting from transfusion. It is necessary to dismiss other causes of acute lung injury (ALI), like sepsis, acute cardiogenic edema, acute respiratory distress syndrome (ARDS) or bacterial infection. There are two mechanisms that lead to the development of this syndrome: immune-mediated and no immune- mediated TRALI. A common theme among the experimental TRALI models is the central importance of neutrophils in mediating the early immune response, and lung vascular injury. Central clinical symptoms are dyspnea, tachypnea, tachycardia, cyanosis and pulmonary secretions, altogether with other hemodynamic alterations, such as hypotension and fever. Complementary to these clinical findings, long-term validated animal models for TRALI should allow the determination of the cellular targets for TRALI-inducing alloantibodies as well as delineation of the underlying pathogenic molecular mechanisms, and key molecular mediators of the pathology. Diagnostic criteria have been established and preventive measures have been implemented. These actions have contributed to the reduction in the overallnumber of fatalities. However, TRALI still remains a clinical problem. Any complication suspected of TRALI should immediately be reported. PMID:26312100

  10. Pressure Controlled Ventilation to Induce Acute Lung Injury in Mice

    PubMed Central

    Koeppen, Michael; Eckle, Tobias; Eltzschig, Holger K.

    2011-01-01

    Murine models are extensively used to investigate acute injuries of different organs systems (1-34). Acute lung injury (ALI), which occurs with prolonged mechanical ventilation, contributes to morbidity and mortality of critical illness, and studies on novel genetic or pharmacological targets are areas of intense investigation (1-3, 5, 8, 26, 30, 33-36). ALI is defined by the acute onset of the disease, which leads to non-cardiac pulmonary edema and subsequent impairment of pulmonary gas exchange (36). We have developed a murine model of ALI by using a pressure-controlled ventilation to induce ventilator-induced lung injury (2). For this purpose, C57BL/6 mice are anesthetized and a tracheotomy is performed followed by induction of ALI via mechanical ventilation. Mice are ventilated in a pressure-controlled setting with an inspiratory peak pressure of 45 mbar over 1 - 3 hours. As outcome parameters, pulmonary edema (wet-to-dry ratio), bronchoalveolar fluid albumin content, bronchoalveolar fluid and pulmonary tissue myeloperoxidase content and pulmonary gas exchange are assessed (2). Using this technique we could show that it sufficiently induces acute lung inflammation and can distinguish between different treatment groups or genotypes (1-3, 5). Therefore this technique may be helpful for researchers who pursue molecular mechanisms involved in ALI using a genetic approach in mice with gene-targeted deletion. PMID:21587159

  11. Acute Aortic Dissection Extending Into the Lung.

    PubMed

    Makdisi, George; Said, Sameh M; Schaff, Hartzell V

    2015-07-01

    The radiologic manifestations of ruptured acute aortic dissection, Stanford type A aortic dissection, DeBakey type 1 can present in different radiographic scenarios with devastating outcomes. Here, we present a rare case of a 70-year-old man who presented to the emergency department with chest pain radiating to the back. A chest computed tomography scan showed a Stanford type A, DeBakey type 1, acute aortic dissection ruptured into the aortopulmonary window and stenosing the pulmonary trunk, both main pulmonary arteries, and dissecting the bronchovascular sheaths and flow into the pulmonary interstitium, causing pulmonary interstitial hemorrhage. The patient underwent emergent ascending aorta replacement with hemiarch replacement with circulatory arrest. The postoperative course was unremarkable. PMID:26140779

  12. Haemodynamic changes in adrenaline-induced acute massive lung oedema.

    PubMed

    Cheng, C P

    1975-01-01

    During the production of adrenaline-induced acute massive lung oedema in the dog, plumonary arterial, pulmonary venous, systemic arterial, and bronchial arterial blood pressures all increase markedly. Pulmonary arterial and venous blood flows fall steeply after initial transient rises. Systemic arterial blood flow also declines, with or without an initial transient increase. The bronchial arterial blood flow shows an initial fall followed by a rise of late onset. The main determinant for the pathogenesis of adrenaline-induced lung oedema is apparently the enormously increased hydrostatic pressure in the pulmonary vascular bed. PMID:123482

  13. NOS-2 Inhibition in Phosgene-Induced Acute Lung Injury

    PubMed Central

    Filipczak, Piotr T.; Senft, Albert P.; Seagrave, JeanClare; Weber, Waylon; Kuehl, Philip J.; Fredenburgh, Laura E.; McDonald, Jacob D.; Baron, Rebecca M.

    2015-01-01

    Phosgene exposure via an industrial or warfare release produces severe acute lung injury (ALI) with high mortality, characterized by massive pulmonary edema, disruption of epithelial tight junctions, surfactant dysfunction, and oxidative stress. There are no targeted treatments for phosgene-induced ALI. Previous studies demonstrated that nitric oxide synthase 2 (NOS-2) is upregulated in the lungs after phosgene exposure; however, the role of NOS-2 in the pathogenesis of phosgene-induced ALI remains unknown. We previously demonstrated that NOS-2 expression in lung epithelium exacerbates inhaled endotoxin-induced ALI in mice, mediated partially through downregulation of surfactant protein B (SP-B) expression. Therefore, we hypothesized that a selective NOS-2 inhibitor delivered to the lung epithelium by inhalation would mitigate phosgene-induced ALI. Inhaled phosgene produced increases in bronchoalveolar lavage fluid protein, histologic lung injury, and lung NOS-2 expression at 24 h. Administration of the selective NOS-2 inhibitor 1400 W via inhalation, but not via systemic delivery, significantly attenuated phosgene-induced ALI and preserved epithelial barrier integrity. Furthermore, aerosolized 1400 W augmented expression of SP-B and prevented downregulation of tight junction protein zonula occludens 1 (ZO-1), both critical for maintenance of normal lung physiology and barrier integrity. We also demonstrate for the first time that NOS-2-derived nitric oxide downregulates the ZO-1 expression at the transcriptional level in human lung epithelial cells, providing a novel target for ameliorating vascular leak in ALI. Our data demonstrate that lung NOS-2 plays a critical role in the development of phosgene-induced ALI and suggest that aerosolized NOS-2 inhibitors offer a novel therapeutic strategy for its treatment. PMID:25870319

  14. Pros and cons of recruitment maneuvers in acute lung injury and acute respiratory distress syndrome.

    PubMed

    Rocco, Patricia R M; Pelosi, Paolo; de Abreu, Marcelo Gama

    2010-08-01

    In patients with acute lung injury and acute respiratory distress syndrome, a protective mechanical ventilation strategy characterized by low tidal volumes has been associated with reduced mortality. However, such a strategy may result in alveolar collapse, leading to cyclic opening and closing of atelectatic alveoli and distal airways. Thus, recruitment maneuvers (RMs) have been used to open up collapsed lungs, while adequate positive end-expiratory pressure (PEEP) levels may counteract alveolar derecruitment during low tidal volume ventilation, improving respiratory function and minimizing ventilator-associated lung injury. Nevertheless, considerable uncertainty remains regarding the appropriateness of RMs. The most commonly used RM is conventional sustained inflation, associated with respiratory and cardiovascular side effects, which may be minimized by newly proposed strategies: prolonged or incremental PEEP elevation; pressure-controlled ventilation with fixed PEEP and increased driving pressure; pressure-controlled ventilation applied with escalating PEEP and constant driving pressure; and long and slow increase in pressure. The efficiency of RMs may be affected by different factors, including the nature and extent of lung injury, capability of increasing inspiratory transpulmonary pressures, patient positioning and cardiac preload. Current evidence suggests that RMs can be used before setting PEEP, after ventilator circuit disconnection or as a rescue maneuver to overcome severe hypoxemia; however, their routine use does not seem to be justified at present. The development of new lung recruitment strategies that have fewer hemodynamic and biological effects on the lungs, as well as randomized clinical trials analyzing the impact of RMs on morbidity and mortality of acute lung injury/acute respiratory distress syndrome patients, are warranted. PMID:20658909

  15. Presumptive acute lung injury following multiple surgeries in a cat

    PubMed Central

    Katayama, Masaaki; Okamura, Yasuhiko; Katayama, Rieko; Sasaki, Jun; Shimamura, Shunsuke; Uzuka, Yuji; Kamishina, Hiroaki; Nezu, Yoshinori

    2013-01-01

    A 12-year-old, 3.5-kg spayed female domestic shorthair cat had a tracheal mass identified as malignant B-cell lymphoma. The cat had tracheal resection and subsequently developed laryngeal paralysis. Due to multiple episodes of respiratory distress the cat subsequently had tracheal surgeries. Finally, the cat had a sudden onset of severe respiratory distress and collapsed. Computed tomography imaging and arterial blood gas analysis supported a diagnosis of acute lung injury. PMID:24082167

  16. [Sodium dichloroisocyanurate-induced acute lung injury in a child].

    PubMed

    Wiel, E; Sicot, J; Leteurtre, S; Binoche, A; Nisse, P; Assez, N

    2013-04-01

    Intoxication, by cyanurate and its chlorated derivatives in children, is increasingly reported in the literature due to accidental ingestion compared to accidental inhalation. We report a case in a 5-year-old child who presented with acute lung injury due to accidental inhalation of gas formed after a reaction of sodium dichloroisocyanurate tablets with water. Prevention remains the best way to reduce the risk of children being intoxicated by inhalation of the gas formed after contact of tablets with water. PMID:23433843

  17. Transfusion-related acute lung injury; clinical perspectives

    PubMed Central

    Kim, Jeongmin

    2015-01-01

    Transfusion-related acute lung injury (TRALI) was introduced in 1983 to describe a clinical syndrome seen within 6 h of a plasma-containing blood products transfusion. TRALI is a rare transfusion complication; however, the FDA has suggested that TRALI is the leading cause of transfusion-related mortality. Understanding the pathogenesis of TRALI will facilitate adopting preventive strategies, such as deferring high plasma volume female product donors. This review outlines the clinical features, pathogenesis, treatment, and prevention of TRALI. PMID:25844126

  18. [Acute lung injury as a consequence of blood transfusion].

    PubMed

    Rodríguez-Moyado, Héctor

    2011-01-01

    Acute lung injury (ALI) has been recognized as a consequence of blood transfusion (BT) since 1978; the Food and Drug Administration, has classified it as the third BT mortality issue, in 2004, and in first place related with ALI. It can be mainly detected as: Acute respiratory distress syndrome (ARDS), transfusion associated circulatory overload (TACO) and transfusion related acute lung injury (TRALI). The clinical onset is: severe dyspnea, bilateral lung infiltration and low oxygen saturation. In USA, ARDS has an incidence of three to 22.4 cases/100 000 inhabitants, with 58.3 % mortality. TACO and TRALI are less frequent; they have been reported according to the number of transfusions: one in 1275 to 6000 for TRALI and one in 356 transfusions for TACO. Mortality is reported from two to 20 % in TRALI and 20 % in TACO. Antileukocyte antibodies in blood donors plasma, caused TRALI in 89 % of cases; also it has been found antigen specificity against leukocyte blood receptor in 59 %. The UCI patients who received a BT have ALI as a complication in 40 % of cases. The capillary pulmonary endothelia is the target of leukocyte antibodies and also plasma biologic modifiers of the stored plasma, most probable like a Sanarelli-Shwar-tzman phenomenon. PMID:21838994

  19. Long-term physiologic outcome after acute farmer's lung

    SciTech Connect

    Cormier, Y.; Belanger, J.

    1985-06-01

    We performed a follow-up study of 61 patients who had an acute episode of farmer's lung (54 men and seven women). Twenty-four subjects had ceased all contact with the barn, while 37 had continued farming. Pulmonary function tests for all subjects showed an initial improvement after the acute episode: 92.4 percent of predicted for carbon monoxide diffusing capacity (Dco) after one year, compared to 61.5 percent at diagnosis; and 6.01 L for total lung capacity (TLC) after three years, compared to 5.35 L. Subsequently, pulmonary function decreased over time. Five years or more after the acute episode, pulmonary function tests in subjects who had continued farm work were not worse than those of subjects who had ceased contact for Dco (68.1 of predicted vs 80.6 percent, respectively and for TLC (5.55 L vs 5.90 L. This study shows that during a long-term follow-up, subjects with farmer's lung who stayed on the farm have subnormal values for pulmonary function but comparable values to those who left their farm.

  20. Prospective Study on the Clinical Course and Outcomes in Transfusion-Related Acute Lung Injury

    PubMed Central

    Looney, Mark R.; Roubinian, Nareg; Gajic, Ognjen; Gropper, Michael A.; Hubmayr, Rolf D.; Lowell, Clifford A.; Bacchetti, Peter; Wilson, Gregory; Koenigsberg, Monique; Lee, Deanna C.; Wu, Ping; Grimes, Barbara; Norris, Philip J.; Murphy, Edward L.; Gandhi, Manish J.; Winters, Jeffrey L.; Mair, David C.; Schuller, Randy M.; Hirschler, Nora V.; Rosen, Rosa Sanchez; Matthay, Michael A.; Toy, Pearl

    2014-01-01

    Objective Transfusion-related acute lung injury is the leading cause of transfusion-related mortality. A prospective study using electronic surveillance was conducted at two academic medical centers in the United States with the objective to define the clinical course and outcomes in transfusion-related acute lung injury cases. Design Prospective case study with controls. Setting University of California, San Francisco and Mayo Clinic, Rochester. Patients We prospectively enrolled 89 patients with transfusion-related acute lung injury, 164 transfused controls, and 145 patients with possible transfusion-related acute lung injury. Interventions None. Measurements and Main Results Patients with transfusion-related acute lung injury had fever, tachycardia, tachypnea, hypotension, and prolonged hypoxemia compared with controls. Of the patients with transfusion-related acute lung injury, 29 of 37 patients (78%) required initiation of mechanical ventilation and 13 of 53 (25%) required initiation of vasopressors. Patients with transfusion-related acute lung injury and possible transfusion-related acute lung injury had an increased duration of mechanical ventilation and increased days in the ICU and hospital compared with controls. There were 15 of 89 patients with transfusion-related acute lung injury (17%) who died, whereas 61 of 145 patients with possible transfusion-related acute lung injury (42%) died and 7 of 164 of controls (4%) died. Patients with transfusion-related acute lung injury had evidence of more systemic inflammation with increases in circulating neutrophils and a decrease in platelets compared with controls. Patients with transfusion-related acute lung injury and possible transfusion-related acute lung injury also had a statistically significant increase in plasma interleukin-8, interleukin-10, and interleukin-1 receptor antagonist posttransfusion compared with controls. Conclusions In conclusion, transfusion-related acute lung injury produced a condition

  1. Thaliporphine derivative improves acute lung injury after traumatic brain injury.

    PubMed

    Chen, Gunng-Shinng; Huang, Kuo-Feng; Huang, Chien-Chu; Wang, Jia-Yi

    2015-01-01

    Acute lung injury (ALI) occurs frequently in patients with severe traumatic brain injury (TBI) and is associated with a poor clinical outcome. Aquaporins (AQPs), particularly AQP1 and AQP4, maintain water balances between the epithelial and microvascular domains of the lung. Since pulmonary edema (PE) usually occurs in the TBI-induced ALI patients, we investigated the effects of a thaliporphine derivative, TM-1, on the expression of AQPs and histological outcomes in the lung following TBI in rats. TM-1 administered (10 mg/kg, intraperitoneal injection) at 3 or 4 h after TBI significantly reduced the elevated mRNA expression and protein levels of AQP1 and AQP4 and diminished the wet/dry weight ratio, which reflects PE, in the lung at 8 and 24 h after TBI. Postinjury TM-1 administration also improved histopathological changes at 8 and 24 h after TBI. PE was accompanied with tissue pathological changes because a positive correlation between the lung injury score and the wet/dry weight ratio in the same animal was observed. Postinjury administration of TM-1 improved ALI and reduced PE at 8 and 24 h following TBI. The pulmonary-protective effect of TM-1 may be attributed to, at least in part, downregulation of AQP1 and AQP4 expression after TBI. PMID:25705683

  2. Hookworm-induced persistent changes to the immunological environment of the lung.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Results from epidemiological and laboratory studies indicate that immunological changes that ensue from a Th2-biased helminth infection result in a decrease in the intensity of subsequent Th2 responses. The Nippostrongylus brasiliensis (Nb) mouse model was used to study molecular and cellular change...

  3. Impact of Preexisting Interstitial Lung Disease on Acute, Extensive Radiation Pneumonitis: Retrospective Analysis of Patients with Lung Cancer

    PubMed Central

    Ozawa, Yuichi; Abe, Takefumi; Omae, Minako; Matsui, Takashi; Kato, Masato; Hasegawa, Hirotsugu; Enomoto, Yasunori; Ishihara, Takeaki; Inui, Naoki; Yamada, Kazunari; Yokomura, Koshi; Suda, Takafumi

    2015-01-01

    Introduction This study investigated the clinical characteristics and predictive factors for developing acute extended radiation pneumonitis with a focus on the presence and radiological characteristics of preexisting interstitial lung disease. Methods Of 1429 irradiations for lung cancer from May 2006 to August 2013, we reviewed 651 irradiations involving the lung field. The presence, compatibility with usual interstitial pneumonia, and occupying area of preexisting interstitial lung disease were retrospectively evaluated by pretreatment computed tomography. Cases of non-infectious, non-cardiogenic, acute respiratory failure with an extended bilateral shadow developing within 30 days after the last irradiation were defined as acute extended radiation pneumonitis. Results Nine (1.4%) patients developed acute extended radiation pneumonitis a mean of 6.7 days after the last irradiation. Although preexisting interstitial lung disease was found in 13% of patients (84 patients), 78% of patients (7 patients) with acute extended radiation pneumonitis cases had preexisting interstitial lung disease, which resulted in incidences of acute extended radiation pneumonitis of 0.35 and 8.3% in patients without and with preexisting interstitial lung disease, respectively. Multivariate logistic analysis indicated that the presence of preexisting interstitial lung disease (odds ratio = 22.6; 95% confidence interval = 5.29–155; p < 0.001) and performance status (≥2; odds ratio = 4.22; 95% confidence interval = 1.06–20.8; p = 0.049) were significant predictive factors. Further analysis of the 84 patients with preexisting interstitial lung disease revealed that involvement of more than 10% of the lung field was the only independent predictive factor associated with the risk of acute extended radiation pneumonitis (odds ratio = 6.14; 95% confidence interval = 1.0–37.4); p = 0.038). Conclusions Pretreatment computed tomography evaluations of the presence of and area size occupied

  4. Acute kidney injury in critically ill patients with lung disease: kidney-lung crosstalk

    PubMed Central

    de Abreu, Krasnalhia Lívia Soares; da Silva Junior, Geraldo Bezerra; Muniz, Thalita Diógenes; Barreto, Adller Gonçalves Costa; Lima, Rafael Siqueira Athayde; Holanda, Marcelo Alcântara; Pereira, Eanes Delgado Barros; Libório, Alexandre Braga; Daher, Elizabeth de Francesco

    2013-01-01

    Objective To examine the factors associated with acute kidney injury and outcome in patients with lung disease. Methods A prospective study was conducted with 100 consecutive patients admitted to a respiratory intensive care unit in Fortaleza (CE), Brazil. The risk factors for acute kidney injury and mortality were investigated in a group of patients with lung diseases. Results The mean age of the study population was 57 years, and 50% were male. The incidence of acute kidney injury was higher in patients with PaO2/FiO2<200 mmHg (54% versus 23.7%; p=0.02). Death was observed in 40 cases and the rate of mortality of the acute kidney injury group was higher (62.8% versus 27.6%; p=0.01). The independent factor that was found to be associated with acute kidney injury was PaO2/FiO2<200 mmHg (p=0.01), and the independent risk factors for death were PEEP at admission (OR: 3.6; 95%CI: 1.3-9.6; p=0.009) and need for hemodialysis (OR: 7.9; 95%CI: 2.2-28.3; p=0.001). Conclusion There was a higher mortality rate in the acute kidney injury group. Increased mortality was associated with mechanical ventilation, high PEEP, urea and need for dialysis. Further studies must be performed to better establish the relationship between kidney and lung injury and its impact on patient outcome. PMID:23917978

  5. Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats

    SciTech Connect

    El-Agamy, Dina S.

    2011-06-01

    The present study aimed to investigate the effect of the new tyrosine kinase inhibitor, nilotinib on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore its possible mechanisms. Male Sprague-Dawley rats were given nilotinib (10 mg/kg) by oral gavage twice daily for 1 week prior to exposure to aerosolized LPS. At 24 h after LPS exposure, bronchoalveolar lavage fluid (BALF) samples and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathological changes in lungs. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) and reduced glutathione (GSH) activities as well as nitrite/nitrate (NO{sub 2}{sup -}/NO{sub 3}{sup -}) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-{alpha} (TNF-{alpha}), transforming growth factor-{beta}{sub 1} (TGF-{beta}{sub 1}) and inducible nitric oxide synthase (iNOS) were determined in lung tissues. Treatment with nilotinib prior to LPS exposure significantly attenuated the LPS-induced pulmonary edema, as it significantly decreased lung W/D ratio, protein concentration and the accumulation of the inflammatory cells in the BALF. This was supported by the histopathological examination which revealed marked attenuation of LPS-induced ALI in nilotinib treated rats. In addition, nilotinib significantly increased SOD and GSH activities with significant decrease in MDA content in the lung. Nilotinib also reduced LPS mediated overproduction of pulmonary NO{sub 2}{sup -}/NO{sub 3}{sup -} levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-{alpha}, TGF-{beta}{sub 1} and iNOS levels in the lung. Taken together, these results demonstrate the protective effects of nilotinib against the LPS-induced ALI. This effect can be attributed to nilotinib ability to counteract the inflammatory cells

  6. Epithelial cell apoptosis causes acute lung injury masquerading as emphysema.

    PubMed

    Mouded, Majd; Egea, Eduardo E; Brown, Matthew J; Hanlon, Shane M; Houghton, A McGarry; Tsai, Larry W; Ingenito, Edward P; Shapiro, Steven D

    2009-10-01

    Theories of emphysema traditionally revolved around proteolytic destruction of extracellular matrix. Models have recently been developed that show airspace enlargement with the induction of pulmonary cell apoptosis. The purpose of this study was to determine the mechanism by which a model of epithelial cell apoptosis caused airspace enlargement. Mice were treated with either intratracheal microcystin (MC) to induce apoptosis, intratracheal porcine pancreatic elastase (PPE), or their respective vehicles. Mice from all groups were inflated and morphometry was measured at various time points. Physiology measurements were performed for airway resistance, tissue elastance, and lung volumes. The groups were further analyzed by air-saline quasistatic measurements, surfactant staining, and surfactant functional studies. Mice treated with MC showed evidence of reversible airspace enlargement. In contrast, PPE-treated mice showed irreversible airspace enlargement. The airspace enlargement in MC-treated mice was associated with an increase in elastic recoil due to an increase in alveolar surface tension. PPE-treated mice showed a loss of lung elastic recoil and normal alveolar surface tension, a pattern more consistent with human emphysema. Airspace enlargement that occurs with the MC model of pulmonary epithelial cell apoptosis displays physiology distinct from human emphysema. Reversibility, restrictive physiology due to changes in surface tension, and alveolar enlargement associated with heterogeneous alveolar collapse are most consistent with a mild acute lung injury. Inflation near total lung capacity gives the appearance of enlarged alveoli as neighboring collapsed alveoli exert tethering forces. PMID:19188661

  7. Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

    PubMed Central

    Kawakami, Takao; Nagasaka, Keiko; Takami, Sachiko; Wada, Kazuya; Tu, Hsiao-Kun; Otsuji, Makiko; Kyono, Yutaka; Dobashi, Tae; Komatsu, Yasuhiko; Kihara, Makoto; Akimoto, Shingo; Peers, Ian S.; South, Marie C.; Higenbottam, Tim; Fukuoka, Masahiro; Nakata, Koichiro; Ohe, Yuichiro; Kudoh, Shoji; Clausen, Ib Groth; Nishimura, Toshihide; Marko-Varga, György; Kato, Harubumi

    2011-01-01

    Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control. PMID:21799770

  8. Simkania negevensis and acute cellular rejection in lung transplant recipients.

    PubMed

    Jamal, Alainna J; Resende, Mariangela R; Prochnow, Taisa; McGilvray, Ian; Pilewski, Joseph M; Crespo, Maria M; Singer, Lianne G; McCurry, Kenneth R; Kolls, Jay K; Keshavjee, Shaf; Liles, W Conrad; Husain, Shahid

    2015-08-01

    Simkania negevensis infection has been hypothesized to play a role in lung transplant rejection. The incidence of S. negevensis infection and its association with acute cellular rejection (ACR) were determined in a prospective cohort study of 78 lung transplant recipients (LTRs) in Toronto, Canada, and Pittsburgh, USA, from July 2007 to January 2010. Simkania negevensis testing was detected by quantitative polymerase chain reaction (PCR) on bronchoalveolar lavage fluid. The relationship between S. negevensis and ACR was examined using Cox proportional hazards models and generalized linear and latent mixed models. Cumulative incidence estimates for time-to-ACR in S. negevensis PCR-positive vs. PCR-negative LTRs were 52.7% vs. 31.1% at six months and 68.9% vs. 44.6% at one yr, respectively. Although not statistically significant, there was a trend toward a higher risk of ACR among S. negevensis PCR-positive vs. PCR-negative LTRs in all statistical models. PMID:26009941

  9. An Intradermal Inoculation Mouse Model for Immunological Investigations of Acute Scrub Typhus and Persistent Infection

    PubMed Central

    Rockx-Brouwer, Dedeke; Xu, Guang; Goez-Rivillas, Yenny; Drom, Claire; Shelite, Thomas R.; Valbuena, Gustavo; Walker, David H.; Bouyer, Donald H.

    2016-01-01

    Scrub typhus is a neglected tropical disease, caused by Orientia tsutsugamushi, a Gram-negative bacterium that is transmitted to mammalian hosts during feeding by Leptotrombidium mites and replicates predominantly within endothelial cells. Most studies of scrub typhus in animal models have utilized either intraperitoneal or intravenous inoculation; however, there is limited information on infection by the natural route in murine model skin or its related early host responses. Here, we developed an intradermal (i.d.) inoculation model of scrub typhus and focused on the kinetics of the host responses in the blood and major infected organs. Following ear inoculation with 6 x 104 O. tsutsugamushi, mice developed fever at 11–12 days post-infection (dpi), followed by marked hypothermia and body weight loss at 14–19 dpi. Bacteria in blood and tissues and histopathological changes were detected around 9 dpi and peaked around 14 dpi. Serum cytokine analyses revealed a mixed Th1/Th2 response, with marked elevations of MCP-1/CCL2, MIP-1α/CCL3 and IL-10 at 9 dpi, followed by increased concentrations of pro-inflammatory markers (IL-6, IL-12, IFN-γ, G-CSF, RANTES/CCL5, KC/CCL11, IL-1α/β, IL-2, TNF-α, GM-CSF), as well as modulatory cytokines (IL-9, IL-13). Cytokine levels in lungs had similar elevation patterns, except for a marked reduction of IL-9. The Orientia 47-kDa gene and infectious bacteria were detected in several organs for up to 84 dpi, indicating persistent infection. This is the first comprehensive report of acute scrub typhus and persistent infection in i.d.-inoculated C57BL/6 mice. This is a significant improvement over current murine models for Orientia infection and will permit detailed studies of host immune responses and infection control interventions. PMID:27479584

  10. An Intradermal Inoculation Mouse Model for Immunological Investigations of Acute Scrub Typhus and Persistent Infection.

    PubMed

    Soong, Lynn; Mendell, Nicole L; Olano, Juan P; Rockx-Brouwer, Dedeke; Xu, Guang; Goez-Rivillas, Yenny; Drom, Claire; Shelite, Thomas R; Valbuena, Gustavo; Walker, David H; Bouyer, Donald H

    2016-08-01

    Scrub typhus is a neglected tropical disease, caused by Orientia tsutsugamushi, a Gram-negative bacterium that is transmitted to mammalian hosts during feeding by Leptotrombidium mites and replicates predominantly within endothelial cells. Most studies of scrub typhus in animal models have utilized either intraperitoneal or intravenous inoculation; however, there is limited information on infection by the natural route in murine model skin or its related early host responses. Here, we developed an intradermal (i.d.) inoculation model of scrub typhus and focused on the kinetics of the host responses in the blood and major infected organs. Following ear inoculation with 6 x 104 O. tsutsugamushi, mice developed fever at 11-12 days post-infection (dpi), followed by marked hypothermia and body weight loss at 14-19 dpi. Bacteria in blood and tissues and histopathological changes were detected around 9 dpi and peaked around 14 dpi. Serum cytokine analyses revealed a mixed Th1/Th2 response, with marked elevations of MCP-1/CCL2, MIP-1α/CCL3 and IL-10 at 9 dpi, followed by increased concentrations of pro-inflammatory markers (IL-6, IL-12, IFN-γ, G-CSF, RANTES/CCL5, KC/CCL11, IL-1α/β, IL-2, TNF-α, GM-CSF), as well as modulatory cytokines (IL-9, IL-13). Cytokine levels in lungs had similar elevation patterns, except for a marked reduction of IL-9. The Orientia 47-kDa gene and infectious bacteria were detected in several organs for up to 84 dpi, indicating persistent infection. This is the first comprehensive report of acute scrub typhus and persistent infection in i.d.-inoculated C57BL/6 mice. This is a significant improvement over current murine models for Orientia infection and will permit detailed studies of host immune responses and infection control interventions. PMID:27479584

  11. Refractory lung metastasis from breast cancer treated with multidisciplinary therapy including an immunological approach.

    PubMed

    Takada, Masahiro; Terunuma, Hiroshi; Deng, Xuewen; Dewan, Md Zahidunnabi; Saji, Shigehira; Kuroi, Katsumasa; Yamamoto, Naoki; Toi, Masakazu

    2011-01-01

    A suggestive case of metastatic disease from breast cancer is reported. The HER-2-positive tumor was refractory to several agents, including anti-HER-2 therapy, trastuzumab, and lapatinib. After re-induction of trastuzumab in combination with activated natural killer (NK) cell injection therapy, tumor markers decreased, and finally a synergistic effect of taxane and capecitabine led to treatment response. This case suggests that multidisciplinary therapy including an immunological approach might be a breakthrough in the treatment of refractory disease. PMID:20354831

  12. Preemptive mechanical ventilation can block progressive acute lung injury

    PubMed Central

    Sadowitz, Benjamin; Jain, Sumeet; Kollisch-Singule, Michaela; Satalin, Joshua; Andrews, Penny; Habashi, Nader; Gatto, Louis A; Nieman, Gary

    2016-01-01

    Mortality from acute respiratory distress syndrome (ARDS) remains unacceptable, approaching 45% in certain high-risk patient populations. Treating fulminant ARDS is currently relegated to supportive care measures only. Thus, the best treatment for ARDS may lie with preventing this syndrome from ever occurring. Clinical studies were examined to determine why ARDS has remained resistant to treatment over the past several decades. In addition, both basic science and clinical studies were examined to determine the impact that early, protective mechanical ventilation may have on preventing the development of ARDS in at-risk patients. Fulminant ARDS is highly resistant to both pharmacologic treatment and methods of mechanical ventilation. However, ARDS is a progressive disease with an early treatment window that can be exploited. In particular, protective mechanical ventilation initiated before the onset of lung injury can prevent the progression to ARDS. Airway pressure release ventilation (APRV) is a novel mechanical ventilation strategy for delivering a protective breath that has been shown to block progressive acute lung injury (ALI) and prevent ALI from progressing to ARDS. ARDS mortality currently remains as high as 45% in some studies. As ARDS is a progressive disease, the key to treatment lies with preventing the disease from ever occurring while it remains subclinical. Early protective mechanical ventilation with APRV appears to offer substantial benefit in this regard and may be the prophylactic treatment of choice for preventing ARDS. PMID:26855896

  13. Preemptive mechanical ventilation can block progressive acute lung injury.

    PubMed

    Sadowitz, Benjamin; Jain, Sumeet; Kollisch-Singule, Michaela; Satalin, Joshua; Andrews, Penny; Habashi, Nader; Gatto, Louis A; Nieman, Gary

    2016-02-01

    Mortality from acute respiratory distress syndrome (ARDS) remains unacceptable, approaching 45% in certain high-risk patient populations. Treating fulminant ARDS is currently relegated to supportive care measures only. Thus, the best treatment for ARDS may lie with preventing this syndrome from ever occurring. Clinical studies were examined to determine why ARDS has remained resistant to treatment over the past several decades. In addition, both basic science and clinical studies were examined to determine the impact that early, protective mechanical ventilation may have on preventing the development of ARDS in at-risk patients. Fulminant ARDS is highly resistant to both pharmacologic treatment and methods of mechanical ventilation. However, ARDS is a progressive disease with an early treatment window that can be exploited. In particular, protective mechanical ventilation initiated before the onset of lung injury can prevent the progression to ARDS. Airway pressure release ventilation (APRV) is a novel mechanical ventilation strategy for delivering a protective breath that has been shown to block progressive acute lung injury (ALI) and prevent ALI from progressing to ARDS. ARDS mortality currently remains as high as 45% in some studies. As ARDS is a progressive disease, the key to treatment lies with preventing the disease from ever occurring while it remains subclinical. Early protective mechanical ventilation with APRV appears to offer substantial benefit in this regard and may be the prophylactic treatment of choice for preventing ARDS. PMID:26855896

  14. Lung Cancer: A Classic Example of Tumor Escape and Progression While Providing Opportunities for Immunological Intervention

    PubMed Central

    Jadus, Martin R.; Natividad, Josephine; Mai, Anthony; Ouyang, Yi; Lambrecht, Nils; Szabo, Sandor; Ge, Lisheng; Hoa, Neil; Dacosta-Iyer, Maria G.

    2012-01-01

    Lung cancers remain one of the most common and deadly cancers in the world today (12.5% of newly diagnosed cancers) despite current advances in chemo- and radiation therapies. Often, by the time these tumors are diagnosed, they have already metastasized. These tumors demonstrate the classic hallmarks of cancer in that they have advanced defensive strategies allowing them to escape various standard oncological treatments. Immunotherapy is making inroads towards effectively treating other fatal cancers, such as melanoma, glioblastoma multiforme, and castrate-resistant prostate cancers. This paper will cover the escape mechanisms of bronchogenic lung cancer that must be overcome before they can be successfully treated. We also review the history of immunotherapy directed towards lung cancers. PMID:22899945

  15. [Role of computed tomography in the diagnosis of acute lung injury/acute respiratory distress syndrome].

    PubMed

    Mazzei, Maria Antonietta; Guerrini, Susanna; Cioffi Squitieri, Nevada; Franchi, Federico; Volterrani, Luca; Genovese, Eugenio Annibale; Macarini, Luca

    2012-11-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a complex pulmonary pathology with high mortality rates, manifesting over a wide range of severity. Clinical diagnosis relies on the following 4 criteria stated by the American-European Consensus Conference: acute onset of impaired gas exchange, severe hypoxemia defined as a PaO2 to FiO2 ratio <300 (PaO2 in mmHg), bilateral diffuse infiltration on chest X-ray; pulmonary artery wedge pressure of ≤18 mmHg to rule out cardiogenic causes of pulmonary edema. The aim of this study was to determine the usefulness of CT in the diagnosis and management of this condition. PMID:23096732

  16. Arctigenin attenuates lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Shi, Xianbao; Sun, Hongzhi; Zhou, Dun; Xi, Huanjiu; Shan, Lina

    2015-04-01

    Arctigenin (ATG) has been reported to possess anti-inflammatory properties. However, the effects of ATG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. In the present study, our investigation was designed to reveal the effect of ATG on LPS-induced ALI in rats. We found that ATG pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-1 (IL-6) in the bronchoalveolar lavage fluid. Furthermore, ATG downregulated the expression of nuclear factor kappa B (NF-κB) p65, promoted the phosphorylation of inhibitor of nuclear factor-κB-α (IκBα) and activated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPKα) in the lung tissues. Our results suggested that ATG attenuates the LPS-induced ALI via activation of AMPK and suppression of NF-κB signaling pathway. PMID:25008149

  17. Escin attenuates acute lung injury induced by endotoxin in mice.

    PubMed

    Xin, Wenyu; Zhang, Leiming; Fan, Huaying; Jiang, Na; Wang, Tian; Fu, Fenghua

    2011-01-18

    Endotoxin causes multiple organ dysfunctions, including acute lung injury (ALI). The current therapeutic strategies for endotoxemia are designed to neutralize one or more of the inflammatory mediators. Accumulating experimental evidence suggests that escin exerts anti-inflammatory and anti-edematous effects. The aim of this study was to evaluate the effect of escin on ALI induced by endotoxin in mice. ALI was induced by injection of lipopolysaccharide (LPS) intravenously. The mice were given dexamethasone or escin before injection of LPS. The mortality rate was recorded. Tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and nitric oxide (NO) were measured. Pulmonary superoxide dismutase (SOD), glutathione peroxidase (GPx) activity, glutathione (GSH), malondialdehyde (MDA) contents, and myeloperoxidase (MPO) activity were also determined. The expression of glucocorticoid receptor (GR) level was detected by Western blotting. Pretreatment with escin could decrease the mortality rate, attenuate lung injury resulted from LPS, down-regulate the level of the inflammation mediators, including NO, TNF-α, and IL-1β, enhance the endogenous antioxidant capacity, and up-regulating the GR expression in lung. The results suggest that escin may have potent protective effect on the LPS-induced ALI by inhibiting of the inflammatory response, and its mechanism involves in up-regulating the GR and enhancing the endogenous antioxidant capacity. PMID:21040784

  18. Inhibition of Neutrophil Exocytosis Ameliorates Acute Lung Injury in Rats

    PubMed Central

    Uriarte, Silvia M.; Rane, Madhavi J.; Merchant, Michael L.; Jin, Shunying; Lentsch, Alex B.; Ward, Richard A.; McLeish, Kenneth R.

    2013-01-01

    Exocytosis of neutrophil granules contributes to acute lung injury (ALI) induced by infection or inflammation, suggesting that inhibition of neutrophil exocytosis in vivo could be a viable therapeutic strategy. This study was conducted to determine the effect of a cell-permeable fusion protein that inhibits neutrophil exocytosis (TAT-SNAP-23) on ALI using an immune complex deposition model in rats. The effect of inhibition of neutrophil exocytosis by intravenous administration of TAT-SNAP-23 on ALI was assessed by albumin leakage, neutrophil infiltration, lung histology, and proteomic analysis of bronchoalveolar lavage fluid (BALf). Administration of TAT-SNAP-23, but not TAT-Control, significantly reduced albumin leakage, total protein levels in the BALf, and intra-alveolar edema and hemorrhage. Evidence that TAT-SNAP-23 inhibits neutrophil exocytosis included a reduction in plasma membrane CD18 expression by BALf neutrophils and a decrease in neutrophil granule proteins in BALf. Similar degree of neutrophil accumulation in the lungs and/or BALf suggests that TAT-SNAP-23 did not alter vascular endothelial cell function. Proteomic analysis of BALf revealed that components of the complement and coagulation pathways were significantly reduced in BALf from TAT-SNAP-23-treated animals. Our results indicate that administration of a TAT-fusion protein that inhibits neutrophil exocytosis reduces in vivo ALI. Targeting neutrophil exocytosis is a potential therapeutic strategy to ameliorate ALI. PMID:23364427

  19. Metabolomics and Its Application to Acute Lung Diseases

    PubMed Central

    Stringer, Kathleen A.; McKay, Ryan T.; Karnovsky, Alla; Quémerais, Bernadette; Lacy, Paige

    2016-01-01

    Metabolomics is a rapidly expanding field of systems biology that is gaining significant attention in many areas of biomedical research. Also known as metabonomics, it comprises the analysis of all small molecules or metabolites that are present within an organism or a specific compartment of the body. Metabolite detection and quantification provide a valuable addition to genomics and proteomics and give unique insights into metabolic changes that occur in tangent to alterations in gene and protein activity that are associated with disease. As a novel approach to understanding disease, metabolomics provides a “snapshot” in time of all metabolites present in a biological sample such as whole blood, plasma, serum, urine, and many other specimens that may be obtained from either patients or experimental models. In this article, we review the burgeoning field of metabolomics in its application to acute lung diseases, specifically pneumonia and acute respiratory disease syndrome (ARDS). We also discuss the potential applications of metabolomics for monitoring exposure to aerosolized environmental toxins. Recent reports have suggested that metabolomics analysis using nuclear magnetic resonance (NMR) and mass spectrometry (MS) approaches may provide clinicians with the opportunity to identify new biomarkers that may predict progression to more severe disease, such as sepsis, which kills many patients each year. In addition, metabolomics may provide more detailed phenotyping of patient heterogeneity, which is needed to achieve the goal of precision medicine. However, although several experimental and clinical metabolomics studies have been conducted assessing the application of the science to acute lung diseases, only incremental progress has been made. Specifically, little is known about the metabolic phenotypes of these illnesses. These data are needed to substantiate metabolomics biomarker credentials so that clinicians can employ them for clinical decision

  20. Metabolomics and Its Application to Acute Lung Diseases.

    PubMed

    Stringer, Kathleen A; McKay, Ryan T; Karnovsky, Alla; Quémerais, Bernadette; Lacy, Paige

    2016-01-01

    Metabolomics is a rapidly expanding field of systems biology that is gaining significant attention in many areas of biomedical research. Also known as metabonomics, it comprises the analysis of all small molecules or metabolites that are present within an organism or a specific compartment of the body. Metabolite detection and quantification provide a valuable addition to genomics and proteomics and give unique insights into metabolic changes that occur in tangent to alterations in gene and protein activity that are associated with disease. As a novel approach to understanding disease, metabolomics provides a "snapshot" in time of all metabolites present in a biological sample such as whole blood, plasma, serum, urine, and many other specimens that may be obtained from either patients or experimental models. In this article, we review the burgeoning field of metabolomics in its application to acute lung diseases, specifically pneumonia and acute respiratory disease syndrome (ARDS). We also discuss the potential applications of metabolomics for monitoring exposure to aerosolized environmental toxins. Recent reports have suggested that metabolomics analysis using nuclear magnetic resonance (NMR) and mass spectrometry (MS) approaches may provide clinicians with the opportunity to identify new biomarkers that may predict progression to more severe disease, such as sepsis, which kills many patients each year. In addition, metabolomics may provide more detailed phenotyping of patient heterogeneity, which is needed to achieve the goal of precision medicine. However, although several experimental and clinical metabolomics studies have been conducted assessing the application of the science to acute lung diseases, only incremental progress has been made. Specifically, little is known about the metabolic phenotypes of these illnesses. These data are needed to substantiate metabolomics biomarker credentials so that clinicians can employ them for clinical decision-making and

  1. Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury.

    PubMed

    Shaver, Ciara M; Grove, Brandon S; Clune, Jennifer K; Mackman, Nigel; Ware, Lorraine B; Bastarache, Julie A

    2016-01-01

    Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF(∆mye), LysM.Cre(+/-)TF(flox/flox)) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI. PMID:26924425

  2. Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury

    PubMed Central

    Shaver, Ciara M.; Grove, Brandon S.; Clune, Jennifer K.; Mackman, Nigel; Ware, Lorraine B.; Bastarache, Julie A.

    2016-01-01

    Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF∆mye, LysM.Cre+/−TFflox/flox) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI. PMID:26924425

  3. Inhaled nitric oxide exacerbated phorbol-induced acute lung injury in rats.

    PubMed

    Lin, Hen I; Chu, Shi Jye; Hsu, Kang; Wang, David

    2004-01-01

    In this study, we determined the effect of inhaled nitric oxide (NO) on the acute lung injury induced by phorbol myristate acetate (PMA) in isolated rat lung. Typical acute lung injury was induced successfully by PMA during 60 min of observation. PMA (2 microg/kg) elicited a significant increase in microvascular permeability, (measured using the capillary filtration coefficient Kfc), lung weight gain, lung weight/body weight ratio, pulmonary arterial pressure (PAP) and protein concentration of the bronchoalveolar lavage fluid. Pretreatment with inhaled NO (30 ppm) significantly exacerbated acute lung injury. All of the parameters reflective of lung injury increased significantly except PAP (P<0.05). Coadministration of Nomega-nitro-L-arginine methyl ester (L-NAME) (5 mM) attenuated the detrimental effect of inhaled NO in PMA-induced lung injury, except for PAP. In addition, L-NAME (5 mM) significantly attenuated PMA-induced acute lung injury except for PAP. These experimental data suggest that inhaled NO significantly exacerbated acute lung injury induced by PMA in rats. L-NAME attenuated the detrimental effect of inhaled NO. PMID:14643171

  4. Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

    PubMed Central

    Gralinski, Lisa E.; Bankhead, Armand; Jeng, Sophia; Menachery, Vineet D.; Proll, Sean; Belisle, Sarah E.; Matzke, Melissa; Webb-Robertson, Bobbie-Jo M.; Luna, Maria L.; Shukla, Anil K.; Ferris, Martin T.; Bolles, Meagan; Chang, Jean; Aicher, Lauri; Waters, Katrina M.; Smith, Richard D.; Metz, Thomas O.; Law, G. Lynn; Katze, Michael G.; McWeeney, Shannon; Baric, Ralph S.

    2013-01-01

    ABSTRACT Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. PMID:23919993

  5. Biomarkers in Acute Lung Injury – Marking Forward Progress

    PubMed Central

    Barnett, Nicolas; Ware, Lorraine B.

    2011-01-01

    In this article we review the ‘state of the art’ with regards to biomarkers for prediction, diagnosis and prognosis in acute lung injury (ALI). We begin by defining biomarkers and the goals of biomarker research in ALI including their ability to define more homogenous populations for recruitment into trials of novel therapies as well as to identify important biological pathways in the pathogenesis of ALI. Progress along four general routes is then examined. First the results of wide-ranging existing protein biomarkers are reported. Secondly, we describe newer biomarkers awaiting or with strong potential for validation. Thirdly, we report progress in the fields of genomics and proteomics. Finally given the complexity and number of potential biomarkers, we examine the results of combining clinical predictors with protein and other biomarkers to produce better prognostic and diagnostic indices. PMID:21742222

  6. [Ph1 positive acute lymphoblastic leukemia with DIC after operation of colon and lung cancer].

    PubMed

    Yashige, H; Fujii, H

    1989-07-01

    We reported a rare case of triple cancers with acute lymphoblastic leukemia (ALL) associated with disseminated intravascular coagulopathy (DIC) after the operations of colon cancer and primary lung cancer. A 78-year-old Japanese male, who had been operated upon for colon cancer (adenocarcinoma) on March 1981, metastatic brain tumor (adenocarcinoma) on December 1986, and primary lung cancer (squamous cell carcinoma) on February 1987, was admitted to our hospital because of severe general malaise on December 6 1987. On admission, he had mild hepatosplenomegaly and hemorrhage diathesis such as purpura. Serum LDH increased to 2,515 mU/ml. The white blood cell count was 6,210/microliters with 53% leukemia cells, and the platelet count was 12,000/microliters. A bone marrow was infiltrated with 96.0% leukemia cells. The leukemia cells stained positively for PAS and negatively for peroxidase. Immunological examination of leukemia cells showed that HLA-DR, TdT, B1 and J5 were positive and cytoplasmic Igmu and surface Ig were negative, indicating common ALL. The coagulation studies revealed that the activated partial thromboplastin time was prolonged to 42.0 seconds, FDP increased to 79.9 micrograms/ml, and antithrombin-III decreased to 62%. Chromosome analysis showed a 48, XY, +2, +21q-, t(9;22) karyotype. He was diagnosed as having Ph1 positive ALL associated with DIC. He was treated with vindesine, prednisolone, L-asparaginase, and adriamycin and complete remission (CR) was achieved after two months. But on August 1988, 8 months after CR, ALL and brain tumor relapsed and he died of pneumonia on September 19, 1988. PMID:2810793

  7. Measuring dead-space in acute lung injury.

    PubMed

    Kallet, R H

    2012-11-01

    Several recent studies have advanced our understanding of dead-space ventilation in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). They have demonstrated the utility of measuring physiologic dead-space-to-tidal volume ratio (VD/VT) and related variables in assessing outcomes as well as therapeutic interventions. These studies have included the evaluation of mortality risk, pulmonary perfusion, as well as the effectiveness of drug therapy, prone positioning, positive end-expiratory pressure (PEEP) titration, and inspiratory pattern in improving gas exchange. In patients with ALI/ARDS managed with lung-protective ventilation a significant relationship between elevated VD/VT and increased mortality continues to be reported in both early and intermediate phases of ALI/ARDS. Some clinical evidence now supports the suggestion that elevated VD/VT in part reflects the severity of pulmonary vascular endothelial damage. Monitoring VD/VT also appears useful in assessing alveolar recruitment when titrating PEEP and may be a particularly expedient method for assessing the effectiveness of prone positioning. It also has revealed how subtle manipulations of inspiratory time and pattern can improve CO(2) excretion. Much of this has been accomplished using volumetric capnography. This allows for more sophisticated measurements of pulmonary gas exchange function including: alveolar VD/VT, the volume of CO(2) excretion and the slope of the alveolar plateau which reflects ventilation: perfusion heterogeneity. Many of these measurements now can be made non-invasively which should only increase the research and clinical utility of volumetric capnography in studying and managing patients with ALI/ARDS. PMID:22858884

  8. Acute Respiratory Distress Syndrome: Role of Oleic Acid-Triggered Lung Injury and Inflammation

    PubMed Central

    Gonçalves-de-Albuquerque, Cassiano Felippe; Silva, Adriana Ribeiro; Burth, Patrícia; Castro-Faria, Mauro Velho; Castro-Faria-Neto, Hugo Caire

    2015-01-01

    Lung injury especially acute respiratory distress syndrome (ARDS) can be triggered by diverse stimuli, including fatty acids and microbes. ARDS affects thousands of people worldwide each year, presenting high mortality rate and having an economic impact. One of the hallmarks of lung injury is edema formation with alveoli flooding. Animal models are used to study lung injury. Oleic acid-induced lung injury is a widely used model resembling the human disease. The oleic acid has been linked to metabolic and inflammatory diseases; here we focus on lung injury. Firstly, we briefly discuss ARDS and secondly we address the mechanisms by which oleic acid triggers lung injury and inflammation. PMID:26640323

  9. Inhibition of lipopolysaccharide induced acute inflammation in lung by chlorination.

    PubMed

    Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani; Qiao, Juan; Lu, Yun

    2016-02-13

    Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies. PMID:26530889

  10. Wogonoside ameliorates lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Zhang, Liang; Ren, Yi; Yang, Chengliang; Guo, Yue; Zhang, Xiaojing; Hou, Gang; Guo, Xinjin; Sun, Nan; Liu, Yongyu

    2014-12-01

    Wogonoside has been reported to have anti-inflammatory properties. In this study, we evaluated the effect of wogonoside on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Male BALB/c mice with ALI, induced by intranasal instillation of LPS, were treated with wogonoside 1 h prior to LPS exposure. Mice treated with LPS alone showed significantly increased TNF-α, IL-6, and IL-1β levels in the bronchoalveolar lavage fluid (BALF). When pretreated with wogonoside, the TNF-α, IL-6, and IL-1β levels were significantly decreased. Meanwhile, wogonoside significantly inhibited LPS-induced increases in the macrophage and neutrophil infiltration of lung tissues and markedly attenuated myeloperoxidase activity. Furthermore, wogonoside inhibited the TLR4 expression and the phosphorylation of NF-κB p65, and IκB induced by LPS. In conclusion, our results indicate that wogonoside exhibits a protective effect on LPS-induced ALI via suppression of TLR4-mediated NF-κB signaling pathways. PMID:24854163

  11. Acanthoic acid ameliorates lipopolysaccharide-induced acute lung injury.

    PubMed

    Qiushi, Wang; Guanghua, Li; Guangquan, Xu

    2015-03-01

    Acanthoic acid, a pimaradiene diterpene isolated from Acanthopanax koreanum, has been reported to have anti-inflammatory activities. However, the effects of acanthoic acid on LPS-induced acute lung injury have not been reported. The purpose of this study was to investigate the protective effect of acanthoic acid on LPS-induced ALI and to clarify the possible anti-inflammatory mechanisms. In vivo, an LPS-induced ALI model in mice was used to assess the protective effects of acanthoic acid on ALI. Meanwhile, mouse alveolar macrophages MH-S were stimulated with LPS in the presence or absence of acanthoic acid. The expressions of TNF-α, IL-6 and IL-1β were measured by ELISA. LXRα and NF-κB expression were detected by Western blot analysis. The results showed that acanthoic acid downregulated LPS-induced TNF-α, IL-6 and IL-1β production in BALF. MPO activity and lung wet-to-dry ratio were also inhibited by acanthoic acid. In addition, acanthoic acid attenuated lung histopathologic changes. In vitro, acanthoic acid inhibited inflammatory cytokines TNF-α, IL-6 and IL-1β production and NF-κB activation in LPS-stimulated alveolar macrophages. Acanthoic acid was found to up-regulated the expression of LXRα. The inhibition of acanthoic acid on LPS-induced cytokines and NF-κB activation can be abolished by LXRα siRNA. In conclusion, our results suggested that the protective effect of acanthoic acid on LPS-induced ALI was due to its ability to activate LXRα, thereby inhibiting LPS-induced inflammatory response. PMID:25620130

  12. Severe physical exertion, oxidative stress, and acute lung injury.

    PubMed

    Shah, Nikunj R; Iqbal, M Bilal; Barlow, Andrew; Bayliss, John

    2011-11-01

    We report the case of a 27-year-old male athlete presenting with severe dyspnoea 24 hours after completing an "Ironman Triathlon." Subsequent chest radiology excluded pulmonary embolus but confirmed an acute lung injury (ALI). Echocardiography corroborated a normal brain natriuretic peptide level by demonstrating good biventricular systolic function with no regional wall motion abnormalities. He recovered well, without requiring ventilatory support, on supplemental oxygen therapy and empirical antibiotics. To date, ALI following severe physical exertion has never been described. Exercise is a form of physiological stress resulting in oxidative stress through generation of reactive oxygen/nitrogen species. In its extreme form, there is potential for an excessive oxidative stress response--one that overwhelms the body's protective antioxidant mechanisms. As our case demonstrated, oxidative stress secondary to severe physical exertion was the most likely factor in the pathogenesis of ALI. Further studies are necessary to explore the pathological consequences of exercise-induced oxidative stress. Although unproven as of yet, further research may be needed to demonstrate if antioxidant therapy can prevent or ameliorate potential life-threatening complications in the acute setting. PMID:22064719

  13. Effect of Thoracentesis on Intubated Patients with Acute Lung Injury.

    PubMed

    Bloom, Matthew B; Serna-Gallegos, Derek; Ault, Mark; Khan, Ahsan; Chung, Rex; Ley, Eric J; Melo, Nicolas; Margulies, Daniel R

    2016-03-01

    Pleural effusions occur frequently in mechanically ventilated patients, but no consensus exists regarding the clinical benefit of effusion drainage. We sought to determine the impact of thoracentesis on gas exchange in patients with differing severities of acute lung injury (ALI). A retrospective analysis was conducted on therapeutic thoracenteses performed on intubated patients in an adult surgical intensive care unit of a tertiary center. Effusions judged by ultrasound to be 400 mL or larger were drained. Subjects were divided into groups based on their initial P:F ratios: normal >300, ALI 200 to 300, and acute respiratory distress syndrome (ARDS) <200. Baseline characteristics, physiologic variables, arterial blood gases, and ventilator settings before and after the intervention were analyzed. The primary end point was the change in measures of oxygenation. Significant improvements in P:F ratios (mean ± SD) were seen only in patients with ARDS (50.4 ± 38.5, P = 0.001) and ALI (90.6 ± 161.7, P = 0.022). Statistically significant improvement was observed in the pO2 (31.1, P = 0.005) and O2 saturation (4.1, P < 0.001) of the ARDS group. The volume of effusion removed did not correlate with changes in individual patient's oxygenation. These data support the role of therapeutic thoracentesis for intubated patients with abnormal P:F ratios. PMID:27099064

  14. Immunologic hemorrhagic pneumonia caused by isocyanates.

    PubMed

    Patterson, R; Nugent, K M; Harris, K E; Eberle, M E

    1990-01-01

    The occurrence of hemoptysis, dyspnea, and bilateral pulmonary opacities progressed to respiratory failure in a 34-yr-old man. Recovery occurred with corticosteroid therapy. In the absence of evidence for an infectious etiology, the possibility of immunologic trimellitic anhydride (TMA) hemorrhagic pneumonitis was considered when the lung biopsy excluded Goodpasture's and other diseases and because the patient was a spray painter. Serologic evaluation for antibodies against TMA was requested. Because the immunologic studies for TMA were negative, and because the patient was a spray painter, immunoassays for three isocyanates conjugated to human serum albumin (HSA) were carried out although there was no specific history of isocyanate exposure at that time. High levels of IgG and IgE antibodies were detected against hexamethylene diisocyanate (HDI)-HSA and toluene diisocyanate (TDI)-HSA. Further investigation documented exposure to spray paint that contained HDI and another isocyanate. The paint was sprayed on warm metal, and subsequently the worker developed an acute illness. Further plant studies were not possible. We propose that the pathogenesis of this case of hemorrhagic pneumonitis is immunologic because of uncontrolled exposure to HDI and TDI, is analogous to the immunologic hemorrhagic pneumonia caused by TMA, and should be considered as a possible cause of a similar acute lung disease after isocyanate exposure. PMID:2153356

  15. Effects of contrast material on computed tomographic measurements of lung volumes in patients with acute lung injury

    PubMed Central

    Bouhemad, Bélaid; Richecoeur, Jack; Lu, Qin; Malbouisson, Luiz M; Cluzel, Philippe; Rouby, Jean-Jacques

    2003-01-01

    Background Intravenous injection of contrast material is routinely performed in order to differentiate nonaerated lung parenchyma from pleural effusion in critically ill patients undergoing thoracic computed tomography (CT). The aim of the present study was to evaluate the effects of contrast material on CT measurement of lung volumes in 14 patients with acute lung injury. Method A spiral thoracic CT scan, consisting of contiguous axial sections of 10 mm thickness, was performed from the apex to the diaphragm at end-expiration both before and 30 s (group 1; n = 7) or 15 min (group 2; n = 7) after injection of 80 ml contrast material. Volumes of gas and tissue, and volumic distribution of CT attenuations were measured before and after injection using specially designed software (Lungview®; Institut National des Télécommunications, Evry, France). The maximal artifactual increase in lung tissue resulting from a hypothetical leakage within the lung of the 80 ml contrast material was calculated. Results Injection of contrast material significantly increased the apparent volume of lung tissue by 83 ± 57 ml in group 1 and 102 ± 80 ml in group 2, whereas the corresponding maximal artifactual increases in lung tissue were 42 ± 52 ml and 31 ± 18 ml. Conclusion Because systematic injection of contrast material increases the amount of extravascular lung water in patients with acute lung injury, it seems prudent to avoid this procedure in critically ill patients undergoing a thoracic CT scan and to reserve its use for specific indications. PMID:12617742

  16. [Continuously alternating prone and supine positioning in acute lung failure].

    PubMed

    Walz, M; Muhr, G

    1992-11-01

    Acute respiratory failure is still one the main problems in surgical intensive care. Unknown pathophysiological mechanisms permit only symptomatic therapy. Today ventilatory strategies by using PEEP und IRV are established to improve gas exchange and FRC by recruiting collapsed alveoli, decreasing intrapulmonary shunting and returning V/Q matching to normal. Furthermore different studies have shown the effects of supine and lateral decubitus posture in patients with acute respiratory failure. There are only rare reports on using the prone position, which doesn't require two-lung ventilation in difference to lateral position. We have studied 16 patients with acute respiratory failure by using continuous changing between prone and supine position under mechanical ventilation. All were male, aged 41.3 years in the middle and showed an average "Injury Severity Score" of 30 (13-50). 15 were trauma patients with blunt chest trauma in 11 cases. We have used prone position on threatening or manifest ARDS. In all patients we observed an increment of PaO2 during prone position on to 48 mmHg so that FiO2 could be reduced on an average of 0.2 within the first 48 h since changing patient's position. Posture changing depends on blood gas analysis, specifically on decreasing PaO2 after previous increment. Patients remained in prone and supine position at a mean of 6.3 (4.5-20) h and posture changing was proceeded over a period of 15.4 (7-32) days. No problems recording to blood pressure or mechanical ventilation appeared during prone position. 11 of 16 patients survived (68.8%), 5 died of cardiac (2) and multi organic failure (3) in connection with sepsis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1458988

  17. Lung ultrasound-a primary survey of the acutely dyspneic patient.

    PubMed

    Lee, Francis Chun Yue

    2016-01-01

    There has been an explosion of knowledge and application of clinical lung ultrasound (LUS) in the last decade. LUS has important applications in the ambulatory, emergency, and critical care settings and its deployability for immediate bedside assessment allows many acute lung conditions to be diagnosed and early interventional decisions made in a matter of minutes. This review detailed the scientific basis of LUS, the examination techniques, and summarises the current applications in several acute lung conditions. It is to be hoped that clinicians, after reviewing the evidence within this article, would see LUS as an important first-line modality in the primary evaluation of an acutely dyspneic patient. PMID:27588206

  18. Immunological, Viral, Environmental, and Individual Factors Modulating Lung Immune Response to Respiratory Syncytial Virus

    PubMed Central

    Bottau, Paolo; Faldella, Giacomo

    2015-01-01

    Respiratory syncytial virus is a worldwide pathogen agent responsible for frequent respiratory tract infections that may become severe and potentially lethal in high risk infants and adults. Several studies have been performed to investigate the immune response that determines the clinical course of the infection. In the present paper, we review the literature on viral, environmental, and host factors influencing virus response; the mechanisms of the immune response; and the action of nonimmunological factors. These mechanisms have often been studied in animal models and in the present review we also summarize the main findings obtained from animal models as well as the limits of each of these models. Understanding the lung response involved in the pathogenesis of these respiratory infections could be useful in improving the preventive strategies against respiratory syncytial virus. PMID:26064963

  19. The serpentine path to a novel mechanism-based inhibitor of acute inflammatory lung injury

    PubMed Central

    2014-01-01

    The Comroe lecture on which this review is based described my research path during the past 45 years, beginning with studies of oxidant stress (hyperoxia) and eventuating in the discovery of a synthetic inhibitor of phospholipase A2 activity (called MJ33) that prevents acute lung injury in mice exposed to lipopolysaccharide. In between were studies of lung ischemia, lung surfactant metabolism, the protein peroxiredoxin 6 and its phospholipase A2 activity, and mechanisms for NADPH oxidase activation. These seemingly unrelated research activities provided the nexus for identification of a novel target and a potentially novel therapeutic agent for prevention or treatment of acute lung injury. PMID:24744383

  20. Anti-radiation vaccine: Immunologically-based Prophylaxis of Acute Toxic Radiation Syndromes Associated with Long-term Space Flight

    NASA Technical Reports Server (NTRS)

    Popov, Dmitri; Maliev, Vecheslav; Jones, Jeffrey; Casey, Rachael C.

    2007-01-01

    Protecting crew from ionizing radiation is a key life sciences problem for long-duration space missions. The three major sources/types of radiation are found in space: galactic cosmic rays, trapped Van Allen belt radiation, and solar particle events. All present varying degrees of hazard to crews; however, exposure to high doses of any of these types of radiation ultimately induce both acute and long-term biological effects. High doses of space radiation can lead to the development of toxicity associated with the acute radiation syndrome (ARS) which could have significant mission impact, and even render the crew incapable of performing flight duties. The creation of efficient radiation protection technologies is considered an important target in space radiobiology, immunology, biochemistry and pharmacology. Two major mechanisms of cellular, organelle, and molecular destruction as a result of radiation exposure have been identified: 1) damage induced directly by incident radiation on the macromolecules they encounter and 2) radiolysis of water and generation of secondary free radicals and reactive oxygen species (ROS), which induce chemical bond breakage, molecular substitutions, and damage to biological molecules and membranes. Free-radical scavengers and antioxidants, which neutralize the damaging activities of ROS, are effective in reducing the impact of small to moderate doses of radiation. In the case of high doses of radiation, antioxidants alone may be inadequate as a radioprotective therapy. However, it remains a valuable component of a more holistic strategy of prophylaxis and therapy. High doses of radiation directly damage biological molecules and modify chemical bond, resulting in the main pathological processes that drive the development of acute radiation syndromes (ARS). Which of two types of radiation-induced cellular lethality that ultimately develops, apoptosis or necrosis, depends on the spectrum of incident radiation, dose, dose rate, and

  1. Monoacylglycerol Lipase (MAGL) Inhibition Attenuates Acute Lung Injury in Mice

    PubMed Central

    Costola-de-Souza, Carolina; Ribeiro, Alison; Ferraz-de-Paula, Viviane; Calefi, Atilio Sersun; Aloia, Thiago Pinheiro Arrais; Gimenes-Júnior, João Antonio; de Almeida, Vinicius Izidio; Pinheiro, Milena Lobão; Palermo-Neto, João

    2013-01-01

    Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG), is mediated by monoacylglycerol lipase (MAGL). The piperidine carbamate, 4-​nitrophenyl- ​4-​(dibenzo[d] [1,3]dioxol-​5-​yl (hydroxy) methyl) piperidine- 1-​carboxylate (JZL184), is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors. Here, we investigated the effects of MAGL inhibition, with a single dose (16 mg/kg, intraperitoneally (i.p.)) of JZL184, in a murine model of lipopolysaccharide (LPS) -induced acute lung injury (ALI) 6, 24 and 48 hours after the inflammatory insult. Treatment with JZL184 decreased the leukocyte migration into the lungs as well as the vascular permeability measured through the bronchoalveolar lavage fluid (BAL) and histological analysis. JZL184 also reduced the cytokine and chemokine levels in the BAL and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281 selective CB1 receptor antagonist (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) and the AM630 selective CB2 receptor antagonist ([6-​iodo-​2-​methyl-​1-​[2-​(4-​morpholinyl)ethyl]-​1H-​indol-​3-​yl](4-​methoxyphenyl)-​methanone) blocked the anti-inflammatory effects previously described for JZL184. It was concluded that MAGL inhibition, and consequently the increase in 2-AG levels, produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 receptors. PMID:24204926

  2. Early Identification of Patients at Risk of Acute Lung Injury

    PubMed Central

    Gajic, Ognjen; Dabbagh, Ousama; Park, Pauline K.; Adesanya, Adebola; Chang, Steven Y.; Hou, Peter; Anderson, Harry; Hoth, J. Jason; Mikkelsen, Mark E.; Gentile, Nina T.; Gong, Michelle N.; Talmor, Daniel; Bajwa, Ednan; Watkins, Timothy R.; Festic, Emir; Yilmaz, Murat; Iscimen, Remzi; Kaufman, David A.; Esper, Annette M.; Sadikot, Ruxana; Douglas, Ivor; Sevransky, Jonathan

    2011-01-01

    Rationale: Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. Objectives: To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). Methods: In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. Measurements and Main Results: Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1–4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78–0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9–5.7). Conclusions: ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772). PMID:20802164

  3. 21 CFR 866.5500 - Hypersensitivity pneumonitis immunological test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... derived from fungal or animal protein sources. When these antibodies react with such dusts in the lung... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological...

  4. 21 CFR 866.5500 - Hypersensitivity pneumonitis immunological test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... derived from fungal or animal protein sources. When these antibodies react with such dusts in the lung... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological...

  5. 21 CFR 866.5500 - Hypersensitivity pneumonitis immunological test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... derived from fungal or animal protein sources. When these antibodies react with such dusts in the lung... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological...

  6. 21 CFR 866.5500 - Hypersensitivity pneumonitis immunological test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... derived from fungal or animal protein sources. When these antibodies react with such dusts in the lung... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological...

  7. Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury

    PubMed Central

    Acosta-Herrera, Marialbert; Lorenzo-Diaz, Fabian; Pino-Yanes, Maria; Corrales, Almudena; Valladares, Francisco; Klassert, Tilman E.; Valladares, Basilio; Slevogt, Hortense; Ma, Shwu-Fan

    2015-01-01

    Acute lung injury (ALI) is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV) using low tidal volumes (LVT) plus moderate to high levels of positive end-expiratory pressure (PEEP). However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg) plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg) plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The ‘response to microorganisms’ was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the ‘neuron projection morphogenesis’ process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated). Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection

  8. Clinical review: Stem cell therapies for acute lung injury/acute respiratory distress syndrome - hope or hype?

    PubMed Central

    2012-01-01

    A growing understanding of the complexity of the pathophysiology of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), coupled with advances in stem cell biology, has led to a renewed interest in the therapeutic potential of stem cells for this devastating disease. Mesenchymal stem cells appear closest to clinical translation, given the evidence that they may favourably modulate the immune response to reduce lung injury, while maintaining host immune-competence and also facilitating lung regeneration and repair. The demonstration that human mesenchymal stem cells exert benefit in the endotoxin-injured human lung is particularly persuasive. Endothelial progenitor cells also demonstrate promise in reducing endothelial damage, which is a key pathophysiological feature of ALI. Embryonic and induced pluripotent stem cells are at an earlier stage in the translational process, but offer the hope of directly replacing injured lung tissue. The lung itself also contains endogenous stem cells, which may ultimately offer the greatest hope for lung diseases, given their physiologic role in replacing and regenerating native lung tissues. However, significant deficits remain in our knowledge regarding the mechanisms of action of stem cells, their efficacy in relevant pre-clinical models, and their safety, particularly in critically ill patients. These gaps need to be addressed before the enormous therapeutic potential of stem cells for ALI/ARDS can be realised. PMID:22424108

  9. Science review: Searching for gene candidates in acute lung injury

    PubMed Central

    Grigoryev, Dmitry N; Finigan, James H; Hassoun, Paul; Garcia, Joe GN

    2004-01-01

    Acute lung injury (ALI) is a complex and devastating illness, often occurring within the setting of sepsis, and carries an annual mortality rate of 30–50%. Although the genetic basis of ALI has not been fully established, an increasing body of evidence suggests that genetic predisposition contributes to disease susceptibility and severity. Significant difficulty exists, however, in defining the exact nature of these genetic factors, including large phenotypic variance, incomplete penetrance, complex gene–environment interactions, and strong potential for locus heterogeneity. We utilized the candidate gene approach and an ortholog gene database to provide relevant gene ontologies and insights into the genetic basis of ALI. We employed a Medline search of selected basic and clinical studies in the English literature and studies sponsored by the HopGene National Institutes of Health sponsored Program in Genomic Applications. Extensive gene expression profiling studies in animal models of ALI (rat, murine, canine), as well as in humans, were performed to identify potential candidate genes . We identified a number of candidate genes for ALI, with blood coagulation and inflammation gene ontologies being the most highly represented. The candidate gene approach coupled with extensive gene profiling and novel bioinformatics approaches is a valuable way to identify genes that are involved in ALI. PMID:15566614

  10. [Fibrinogen--acute phase protein as a marker of immunological process as atherosclerosis].

    PubMed

    Rajtari, Renata; Kloch, Małgorzata; Kiec-Wilk, Beata; Kolasińska-Kloch, Władysława

    2005-01-01

    The most important CAD risk factors are: smoking, high level of LDL-cholesterol and low level of HDL-cholesterol, hypertriglyceridemia, diabetes, obesity, hypertension, men sex, age over 45 in men and over 55 in women. Carl von Rokitański was the first who suggested the role of thrombosis and fibrynolisis in the development of atherosclerosis and was the author of thrombolic theory. The recently studies show that atherosclerosis is an immuno-inflamatory process. Fibrinogen as an acute phase protein is a new marker of ischemic heart disease and its role in atherosclerosis needs further investigations. PMID:17037285

  11. Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor.

    PubMed

    Shaver, Ciara M; Grove, Brandon S; Putz, Nathan D; Clune, Jennifer K; Lawson, William E; Carnahan, Robert H; Mackman, Nigel; Ware, Lorraine B; Bastarache, Julie A

    2015-11-01

    Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI. PMID:25884207

  12. Redistribution of pulmonary blood flow impacts thermodilution-based extravascular lung water measurements in a model of acute lung injury

    PubMed Central

    Easley, R. Blaine; Mulreany, Daniel G.; Lancaster, Christopher T.; Custer, Jason W.; Fernandez-Bustamante, Ana; Colantuoni, Elizabeth; Simon, Brett A.

    2009-01-01

    Background Studies using transthoracic thermodilution have demonstrated increased extravascular lung water (EVLW) measurements attributed to progression of edema and flooding during sepsis and acute lung injury. We hypothesize that redistribution of pulmonary blood flow can cause increased apparent EVLW secondary to increased perfusion of thermally silent tissue, not increased lung edema. Methods Anesthetized, mechanically ventilated canines were instrumented with PiCCO® (Pulsion Medical, Munich, Germany) catheters and underwent lung injury by repetitive saline lavage. Hemodynamic and respiratory physiologic data were recorded. After stabilized lung injury, endotoxin was administered to inactivate hypoxic pulmonary vasoconstriction. Computerized tomographic imaging was performed to quantify in vivo lung volume, total tissue (fluid) and air content, and regional distribution of blood flow. Results Lavage injury caused an increase in airway pressures and decreased arterial oxygen content with minimal hemodynamic effects. EVLW and shunt fraction increased after injury and then markedly following endotoxin administration. Computerized tomographic measurements quantified an endotoxin-induced increase in pulmonary blood flow to poorly aerated regions with no change in total lung tissue volume. Conclusions The abrupt increase in EVLW and shunt fraction after endotoxin administration is consistent with inactivation of hypoxic pulmonary vasoconstriction and increased perfusion to already flooded lung regions that were previously thermally silent. Computerized tomographic studies further demonstrate in vivo alterations in regional blood flow (but not lung water) and account for these alterations in shunt fraction and EVLW. PMID:19809280

  13. Amniotic Fluid Stem Cells from EGFP Transgenic Mice Attenuate Hyperoxia-Induced Acute Lung Injury

    PubMed Central

    Lai, Cheng-Wei; Yen, Chih-Ching; Lee, Kun-Hsiung; Wu, Shinn-Chih; Chen, Chuan-Mu

    2013-01-01

    High concentrations of oxygen aggravate the severity of lung injury in patients requiring mechanical ventilation. Although mesenchymal stem cells have been shown to effectively attenuate various injured tissues, there is limited information regarding a role for amniotic fluid stem cells (AFSCs) in treating acute lung injury. We hypothesized that intravenous delivery of AFSCs would attenuate lung injury in an experimental model of hyperoxia-induced lung injury. AFSCs were isolated from EGFP transgenic mice. The in vitro differentiation, surface markers, and migration of the AFSCs were assessed by specific staining, flow cytometry, and a co-culture system, respectively. The in vivo therapeutic potential of AFSCs was evaluated in a model of acute hyperoxia-induced lung injury in mice. The administration of AFSCs significantly reduced the hyperoxia-induced pulmonary inflammation, as reflected by significant reductions in lung wet/dry ratio, neutrophil counts, and the level of apoptosis, as well as reducing the levels of inflammatory cytokine (IL-1β, IL-6, and TNF-α) and early-stage fibrosis in lung tissues. Moreover, EGFP-expressing AFSCs were detected and engrafted into a peripheral lung epithelial cell lineage by fluorescence microscopy and DAPI stain. Intravenous administration of AFSCs may offer a new therapeutic strategy for acute lung injury (ALI), for which efficient treatments are currently unavailable. PMID:24040409

  14. Some immunological properties of lymphoid cells from patients with acute lymphatic leukaemia (ALL)

    PubMed Central

    Melief, C. J. M.; Schweitzer, Marjan; Zeylemaker, W. P.; Verhagen, E. H.; Eijsvoogel, V. P.

    1973-01-01

    The in vitro responses of lymphoid cells from the blood of children with acute lymphatic leukaemia to stimulation with phytohaemagglutinin, pokeweed mitogen, allogeneic lymphocytes and a cocktail of five different antigens were studied. In addition the stimulatory capacity in mixed lymphocyte culture was investigated as well as the formation of rosettes with sheep erythrocytes which were either uncoated or coated with antibody and complement. Whereas lymphocytes from acute lymphatic leukaemia patients in remission responded well to all stimuli tested, lymphoid cells from all seven patients in leukaemic stages with at least 80% lymphatic cells in the differential leucocyte count uniformly displayed strongly reduced or even absent responses. The phytohaemagglutinin response of cells from leukaemic stages was not only reduced but also delayed and the stimulatory capacity in mixed lymphocyte culture was always stronger than the responding capacity. These data indicate that the responses of cells from leukaemic stages are due to the presence of a small proportion of residual normal lymphocytes whereas the leukaemic cells themselves are unable to respond. The stimulatory capacity in mixed lymphocyte culture was reduced in four cases. The cells from two patients, however, displayed increased stimulatory capacity. The cells from different patients varied strongly with respect to the presence of surface markers as tested by rosette formation with sheep erythrocytes either uncoated or coated with antibody and complement. PMID:4520119

  15. What has been learnt from P/V curves in patients with acute lung injury/acute respiratory distress syndrome.

    PubMed

    Maggiore, S M; Richard, J C; Brochard, L

    2003-08-01

    Mechanical impairment of the respiratory system was recognised soon after the description of acute respiratory distress syndrome. The analysis of the pressure/volume (P/V) curve of the respiratory system contributed a lot to the understanding of the pathophysiology of acute lung injury and formed the basis for lung protection. The lower and upper inflection points were regarded as points of interest to avoid cyclic derecruitment and overdistension and to optimise ventilatory settings. However, because of the heterogeneity of lung injury, reducing the mechanical properties of the whole respiratory system to a single curve is a schematic approach, which makes interpretation difficult. New data suggest that alveolar re-inflation occurs along the whole P/V curve that can, therefore, be considered as a recruitment curve. The lower inflection point has no relationship with alveolar opening and closure and does not indicate the positive end-expiratory pressure needed to prevent alveolar collapse. The shape of the P/V curve gives information about the extension and the homogeneity of lung injury, indicating the possibility of lung recruitment. The upper inflection point, classically seen as the beginning of overdistension, may also indicate the end of recruitment. The pressure/volume curve offers the unique opportunity of evaluating alveolar recruitment/derecruitment at the bedside that can be helpful for the identification of optimal ventilatory settings and makes the curve a valuable tool for the ventilatory management of acute lung injury. PMID:12945997

  16. Critical care in the ED: potentially fatal asthma and acute lung injury syndrome

    PubMed Central

    Hodder, Rick

    2012-01-01

    Emergency department clinicians are frequently called upon to assess, diagnose, and stabilize patients who present with acute respiratory failure. This review describes a rapid initial approach to acute respiratory failure in adults, illustrated by two common examples: (1) an airway disease – acute potentially fatal asthma, and (2) a pulmonary parenchymal disease – acute lung injury/acute respiratory distress syndrome. As such patients are usually admitted to hospital, discussion will be focused on those initial management aspects most relevant to the emergency department clinician. PMID:27147862

  17. Immunology of infusion reactions in the treatment of patients with acute lymphoblastic leukemia.

    PubMed

    Asselin, Barbara

    2016-07-01

    Infusion reactions are potentially dose-limiting adverse events associated with intravenous administration of several common agents used to treat patients with acute lymphoblastic leukemia. True clinical hypersensitivity reactions are antibody-mediated and can occur only after repeated exposure to an antigen. Conversely, anaphylactoid infusion reactions are nonantibody-mediated and often occur on the initial exposure to a drug. Cytokine-release syndrome comprises a subset of nonantibody-mediated infusion reactions associated with the use of monoclonal antibodies and immune therapies. Clinical symptoms of hypersensitivity reactions and nonantibody-mediated infusion reactions heavily overlap and can be difficult to distinguish in practice. Regardless of the underlying mechanism, any infusion reaction can negatively affect treatment efficacy and patient safety. These events require prompt response, and potentially, modification of subsequent therapy. PMID:27086555

  18. Treatment of acute lung injury by targeting MG53-mediated cell membrane repair.

    PubMed

    Jia, Yanlin; Chen, Ken; Lin, Peihui; Lieber, Gissela; Nishi, Miyuki; Yan, Rosalie; Wang, Zhen; Yao, Yonggang; Li, Yu; Whitson, Bryan A; Duann, Pu; Li, Haichang; Zhou, Xinyu; Zhu, Hua; Takeshima, Hiroshi; Hunter, John C; McLeod, Robbie L; Weisleder, Noah; Zeng, Chunyu; Ma, Jianjie

    2014-01-01

    Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischaemia-reperfusion and overventilation-induced injury to the lung when compared with wild-type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases. PMID:25034454

  19. MicroRNA Regulation of Acute Lung Injury and Acute Respiratory Distress Syndrome.

    PubMed

    Rajasekaran, Subbiah; Pattarayan, Dhamotharan; Rajaguru, P; Sudhakar Gandhi, P S; Thimmulappa, Rajesh K

    2016-10-01

    The acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), is a very common condition associated with critically ill patients, which causes substantial morbidity and mortality worldwide. Despite decades of research, effective therapeutic strategies for clinical ALI/ARDS are not available. In recent years, microRNAs (miRNAs), small non-coding molecules have emerged as a major area of biomedical research as they post-transcriptionally regulate gene expression in diverse biological and pathological processes, including ALI/ARDS. In this context, this present review summarizes a large body of evidence implicating miRNAs and their target molecules in ALI/ARDS originating largely from studies using animal and cell culture model systems of ALI/ARDS. We have also focused on the involvement of miRNAs in macrophage polarization, which play a critical role in regulating the pathogenesis of ALI/ARDS. Finally, the possible future directions that might lead to novel therapeutic strategies for the treatment of ALI/ARDS are also reviewed. J. Cell. Physiol. 231: 2097-2106, 2016. © 2016 Wiley Periodicals, Inc. PMID:26790856

  20. Effects of acute and chronic administration of methylprednisolone on oxidative stress in rat lungs* **

    PubMed Central

    Torres, Ronaldo Lopes; Torres, Iraci Lucena da Silva; Laste, Gabriela; Ferreira, Maria Beatriz Cardoso; Cardoso, Paulo Francisco Guerreiro; Belló-Klein, Adriane

    2014-01-01

    Objective: To determine the effects of acute and chronic administration of methylprednisolone on oxidative stress, as quantified by measuring lipid peroxidation (LPO) and total reactive antioxidant potential (TRAP), in rat lungs. Methods: Forty Wistar rats were divided into four groups: acute treatment, comprising rats receiving a single injection of methylprednisolone (50 mg/kg i.p.); acute control, comprising rats i.p. injected with saline; chronic treatment, comprising rats receiving methylprednisolone in drinking water (6 mg/kg per day for 30 days); and chronic control, comprising rats receiving normal drinking water. Results: The levels of TRAP were significantly higher in the acute treatment group rats than in the acute control rats, suggesting an improvement in the pulmonary defenses of the former. The levels of lung LPO were significantly higher in the chronic treatment group rats than in the chronic control rats, indicating oxidative damage in the lung tissue of the former. Conclusions: Our results suggest that the acute use of corticosteroids is beneficial to lung tissue, whereas their chronic use is not. The chronic use of methylprednisolone appears to increase lung LPO levels. PMID:25029646

  1. Alcohol Worsens Acute Lung Injury by Inhibiting Alveolar Sodium Transport through the Adenosine A1 Receptor

    PubMed Central

    Urich, Daniela; Soberanes, Saul; Manghi, Tomas S.; Chiarella, Sergio E.; Chandel, Navdeep S.; Budinger, G. R. Scott; Mutlu, Gökhan M.

    2012-01-01

    Objective Alcohol intake increases the risk of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) and is associated with poor outcomes in patients who develop these syndromes. No specific therapies are currently available to treat or decrease the risk of ARDS in patients with alcoholism. We have recently shown increased levels of lung adenosine inhibit alveolar fluid clearance, an important predictor of outcome in patients with ARDS. We hypothesized that alcohol might worsen lung injury by increasing lung adenosine levels, resulting in impaired active Na+ transport in the lung. Methods We treated wild-type mice with alcohol administered i.p. to achieve blood alcohol levels associated with moderate to severe intoxication and measured the rate of alveolar fluid clearance and Na,K-ATPase expression in peripheral lung tissue and assessed the effect of alcohol on survival during exposure to hyperoxia. We used primary rat alveolar type II cells to investigate the mechanisms by which alcohol regulates alveolar Na+ transport. Results Exposure to alcohol reduced alveolar fluid clearance, downregulated Na,K-ATPase in the lung tissue and worsened hyperoxia-induced lung injury. Alcohol caused an increase in BAL fluid adenosine levels. A similar increase in lung adenosine levels was observed after exposure to hyperoxia. In primary rat alveolar type II cells alcohol and adenosine decreased the abundance of the Na,K-ATPase at the basolateral membrane via a mechanism that required activation of the AMPK. Conclusions Alcohol decreases alveolar fluid clearance and impairs survival from acute lung injury. Alcohol induced increases in lung adenosine levels may be responsible for reduction in alveolar fluid clearance and associated worsening of lung injury. PMID:22272351

  2. Depressive Symptoms and Impaired Physical Function after Acute Lung Injury

    PubMed Central

    Colantuoni, Elizabeth; Mendez-Tellez, Pedro A.; Dinglas, Victor D.; Shanholtz, Carl; Husain, Nadia; Dennison, Cheryl R.; Herridge, Margaret S.; Pronovost, Peter J.; Needham, Dale M.

    2012-01-01

    Rationale: Survivors of acute lung injury (ALI) frequently have substantial depressive symptoms and physical impairment, but the longitudinal epidemiology of these conditions remains unclear. Objectives: To evaluate the 2-year incidence and duration of depressive symptoms and physical impairment after ALI, as well as risk factors for these conditions. Methods: This prospective, longitudinal cohort study recruited patients from 13 intensive care units (ICUs) in four hospitals, with follow-up 3, 6, 12, and 24 months after ALI. The outcomes were Hospital Anxiety and Depression Scale depression score greater than or equal to 8 (“depressive symptoms”) in patients without a history of depression before ALI, and two or more dependencies in instrumental activities of daily living (“impaired physical function”) in patients without baseline impairment. Measurements and Main Results: During 2-year follow-up of 186 ALI survivors, the cumulative incidences of depressive symptoms and impaired physical function were 40 and 66%, respectively, with greatest incidence by 3-month follow-up; modal durations were greater than 21 months for each outcome. Risk factors for incident depressive symptoms were education 12 years or less, baseline disability or unemployment, higher baseline medical comorbidity, and lower blood glucose in the ICU. Risk factors for incident impaired physical function were longer ICU stay and prior depressive symptoms. Conclusions: Incident depressive symptoms and impaired physical function are common and long-lasting during the first 2 years after ALI. Interventions targeting potentially modifiable risk factors (e.g., substantial depressive symptoms in early recovery) should be evaluated to improve ALI survivors’ long-term outcomes. PMID:22161158

  3. Sex, Race, and the Development of Acute Lung Injury

    PubMed Central

    Lemos-Filho, Luciano B.; Mikkelsen, Mark E.; Martin, Greg S.; Dabbagh, Ousama; Adesanya, Adebola; Gentile, Nina; Esper, Annette; Gajic, Ognjen

    2013-01-01

    Background: Prior studies suggest that mortality differs by sex and race in patients who develop acute lung injury (ALI). Whether differences in presentation account for these disparities remains unclear. We sought to determine whether sexual and racial differences exist in the rate of ALI development and ALI-related mortality after accounting for differences in clinical presentations. Methods: This was a multicenter, observational cohort study of 5,201 patients at risk for ALI. Multivariable logistic regression with adjustment for center-level effects was used to adjust for potential covariates. Results: The incidence of ALI development was 5.9%; in-hospital mortality was 5.0% for the entire cohort, and 24.4% for those patients who developed ALI. Men were more likely to develop ALI compared to women (6.9% vs 4.7%, P < .001) and had a nonsignificant increase in mortality when ALI developed (27.6% vs 18.5%, P = .08). However, after adjustment for baseline imbalances between sexes these differences were no longer significant. Black patients, compared to white patients, presented more frequently with pneumonia, sepsis, or shock and had higher severity of illness. Black patients were less likely to develop ALI than whites (4.5% vs. 6.5%, P = .014), and this association remained statistically significant after adjusting for differences in presentation (OR, 0.66; 95 % CI, 0.45-0.96). Conclusions: Sex and race differences exist in the clinical presentation of patients at risk of developing ALI. After accounting for differences in presentation, there was no sex difference in ALI development and outcome. Black patients were less likely to develop ALI despite increased severity of illness on presentation. PMID:23117155

  4. [Lung ultrasound in acute and critical care medicine].

    PubMed

    Zechner, P M; Seibel, A; Aichinger, G; Steigerwald, M; Dorr, K; Scheiermann, P; Schellhaas, S; Cuca, C; Breitkreutz, R

    2012-07-01

    The development of modern critical care lung ultrasound is based on the classical representation of anatomical structures and the need for the assessment of specific sonography artefacts and phenomena. The air and fluid content of the lungs is interpreted using few typical artefacts and phenomena, with which the most important differential diagnoses can be made. According to a recent international consensus conference these include lung sliding, lung pulse, B-lines, lung point, reverberation artefacts, subpleural consolidations and intrapleural fluid collections. An increased number of B-lines is an unspecific sign for an increased quantity of fluid in the lungs resembling interstitial syndromes, for example in the case of cardiogenic pulmonary edema or lung contusion. In the diagnosis of interstitial syndromes lung ultrasound provides higher diagnostic accuracy (95%) than auscultation (55%) and chest radiography (72%). Diagnosis of pneumonia and pulmonary embolism can be achieved at the bedside by evaluating subpleural lung consolidations. Detection of lung sliding can help to detect asymmetrical ventilation and allows the exclusion of a pneumothorax. Ultrasound-based diagnosis of pneumothorax is superior to supine anterior chest radiography: for ultrasound the sensitivity is 92-100% and the specificity 91-100%. For the diagnosis of pneumothorax a simple algorithm was therefore designed: in the presence of lung sliding, lung pulse or B-lines, pneumothorax can be ruled out, in contrast a positive lung point is a highly specific sign of the presence of pneumothorax. Furthermore, lung ultrasound allows not only diagnosis of pleural effusion with significantly higher sensitivity than chest x-ray but also visual control in ultrasound-guided thoracocentesis. PMID:22772347

  5. The role of leukocytes in the pathogenesis of fibrin deposition in bovine acute lung injury.

    PubMed Central

    Car, B. D.; Suyemoto, M. M.; Neilsen, N. R.; Slauson, D. O.

    1991-01-01

    The peculiarly fibrinous nature of bovine acute lung injury due to infection with Pasteurella haemolytica A1 suggests an imbalance between leukocyte-directed procoagulant and profibrinolytic influences in the inflamed bovine lung. Calves with experimental pneumonia produced by intratracheal inoculation with P. haemolytica A1 developed acute locally extensive cranioventral fibrinopurulent bronchopneumonia. Pulmonary alveolar macrophages (PAM) recovered by segmental lavage from affected lung lobes were 30 times more procoagulant than PAM obtained from unaffected lung lobes and 37-fold more procoagulant than PAM from control calf lungs. Unlike the enhancement of procoagulant activity, profibrinolytic activity (plasminogen activator amidolysis) of total lung leukocytes (PAM and plasminogen activator neutrophils [PMN]) was decreased 23 times in cells obtained from affected lung lobes and also was decreased four times in cells obtained from unaffected lobes of infected animals. This marked imbalance in cellular procoagulant and fibrinolytic activity probably contributes significantly to enhanced fibrin deposition and retarded fibrin removal. In addition, PAM from inflamed lungs were strongly positive for bovine tissue factor antigen as demonstrated by immunocytochemistry. Intensely tissue factor-positive PAM enmeshed in fibrinocellular exudates and positive alveolar walls were situated such that they were likely to have, in concert, initiated extrinsic activation of coagulation in the acutely inflamed lung. These data collectively suggest that enhanced PAM-directed procoagulant activity and diminished PAM- and PMN-directed profibrinolytic activity represent important modifications of local leukocyte function in bovine acute lung injury that are central to the pathogenesis of lesion development with extensive fibrin deposition and retarded fibrin removal. Images Figure 2 Figure 3 PMID:2024707

  6. Antiradiation Antitoxin IgG : Immunological neutralization of Radiation Toxins at Acute Radiation Syndromes.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Slava

    Introduction: High doses of radiation induce apoptotic necrosis of radio-sensitive cells. Mild doses of radiation induce apoptosis or controlled programmed death of radio-sensitive cells with-out development of inflammation and formation of Radiation Toxins. Cell apoptotic necrosis initiates Radiation Toxins (RT)formation. Radiation Toxins play an important role as a trig-ger mechanism for inflammation development and cell lysis. If an immunotherapy approach to treatment of the acute radiation syndromes (ARS) were to be developed, a consideration could be given to neutralization of radiation toxins (Specific Radiation Determinants-SRD) by specific antiradiation antibodies. Therapeutic neutralization effects of the blocking anti-radiation antibodies on the circulated RT had been studied. Radiation Toxins were isolated from the central lymph of irradiated animals with Cerebrovascular(Cv ARS),Cardiovascular (Cr ARS),Gastrointestinal(Gi ARS) and Haemopoietic (Hp ARS) forms of ARS. To accomplish this objective, irradiated animals were injected with a preparation of anti-radiation immunoglobulin G (IgG) obtained from hyperimmune donors. Radiation-induced toxins that we call Specific Radiation Determinants (SRD) possess toxic (neurotoxic, haemotoxic) characteristics as well as specific antigenic properties. Depending on direct physiochemical radiation damage, they can induce development of many of the pathological processes associated with ARS. We have tested several specific hyperimmune IgG preparations against these radiation toxins and ob-served that their toxic properties were neutralized by the specific antiradiation IgGs. Material and Methods: A scheme of experiments was following: 1.Isolation of radiation toxins (RT) from the central lymph of irradiated animals with different form of ARS. 2.Transformation of a toxic form of the RT to a toxoid form of the RT. 3.Immunization of radiation naive animals. Four groups of rabbits were inoculated with a toxoid form of SRD

  7. THE 5-LIPOXYGENASE PATHWAY IS REQUIRED FOR ACUTE LUNG INJURY FOLLOWING HEMORRHAGIC SHOCK

    PubMed Central

    Eun, John C.; Moore, Ernest E.; Mauchley, David C.; Johnson, Chris A.; Meng, Xianzhong; Banerjee, Anirban; Wohlauer, Max V.; Zarini, Simona; Gijón, Miguel A.; Murphy, Robert C.

    2012-01-01

    The cellular and biochemical mechanisms leading to acute lung injury and subsequent multiple organ failure are only partially understood. In order to study the potential role of eicosanoids, particularly leukotrienes, as possible mediators of acute lung injury, we used a murine experimental model of acute lung injury induced by hemorrhagic shock after blood removal via cardiac puncture. Neutrophil sequestration as shown by immunofluorescence, and protein leakage into the alveolar space, were measured as markers of injury. We used liquid chromatography coupled to tandem mass spectrometry to unequivocally identify several eicosanoids in the bronchoalveolar lavage fluid of experimental animals. MK886, a specific inhibitor of the 5-lipoxygenase pathway, as well as transgenic mice deficient in 5-lipoxygenase, were used to determine the role of this enzymatic pathway in this model. Leukotriene B4 and leukotriene C4 were consistently elevated in shock-treated mice compared to sham-treated mice. MK886 attenuated neutrophil infiltration and protein extravasation induced by hemorrhagic shock. 5-lipoxygenase-deficient mice showed reduced neutrophil infiltration and protein extravasation after shock treatment, indicating greatly reduced lung injury. These results support the hypothesis that 5-lipoxygenase, most likely through the generation of leukotrienes, plays an important role in the pathogenesis of acute lung injury induced by hemorrhagic shock in mice. This pathway could represent a new target for pharmacological intervention to reduce lung damage following severe primary injury. PMID:22392149

  8. Functional genomics of chlorine-induced acute lung injury in mice.

    PubMed

    Leikauf, George D; Pope-Varsalona, Hannah; Concel, Vincent J; Liu, Pengyuan; Bein, Kiflai; Brant, Kelly A; Dopico, Richard A; Di, Y Peter; Jang, An-Soo; Dietsch, Maggie; Medvedovic, Mario; Li, Qian; Vuga, Louis J; Kaminski, Naftali; You, Ming; Prows, Daniel R

    2010-07-01

    Acute lung injury can be induced indirectly (e.g., sepsis) or directly (e.g., chlorine inhalation). Because treatment is still limited to supportive measures, mortality remains high ( approximately 74,500 deaths/yr). In the past, accidental (railroad derailments) and intentional (Iraq terrorism) chlorine exposures have led to deaths and hospitalizations from acute lung injury. To better understand the molecular events controlling chlorine-induced acute lung injury, we have developed a functional genomics approach using inbred mice strains. Various mouse strains were exposed to chlorine (45 ppm x 24 h) and survival was monitored. The most divergent strains varied by more than threefold in mean survival time, supporting the likelihood of an underlying genetic basis of susceptibility. These divergent strains are excellent models for additional genetic analysis to identify critical candidate genes controlling chlorine-induced acute lung injury. Gene-targeted mice then could be used to test the functional significance of susceptibility candidate genes, which could be valuable in revealing novel insights into the biology of acute lung injury. PMID:20601635

  9. Asialoerythropoietin ameliorates bleomycin-induced acute lung injury in rabbits by reducing inflammation.

    PubMed

    Sonoda, Akinaga; Nitta, Norihisa; Tsuchiya, Keiko; Otani, Hideji; Watanabe, Shobu; Mukaisho, Kenichi; Tomozawa, Yuki; Nagatani, Yukihiro; Ohta, Shinichi; Takahashi, Masashi; Murata, Kiyoshi

    2014-11-01

    Acute lung injury, a critical illness characterized by acute respiratory failure with bilateral pulmonary infiltrates, remains unresponsive to current treatments. The condition involves injury to the alveolar capillary barrier, neutrophil accumulation and the induction of proinflammatory cytokines followed by lung fibrosis. In the present study, a rabbit model of bleomycin-induced acute lung injury was established to examine the effects of asialoerythropoietin (AEP), an agent with tissue-protective activities, on pulmonary inflammation. Six Japanese white rabbits were randomly divided into two equal groups. Acute lung injury was induced in all rabbits by intratracheally injecting bleomycin. The control group was injected with bleomycin only; the experimental (AEP) group was injected intravenously with AEP (80 μg/kg) prior to the bleomycin injection. Computed tomography (CT) studies were performed seven days later. The CT inflammatory scores of areas exhibiting abnormal density and the pathological inflammatory scores were recorded as a ratio on a 7×7 mm grid. The CT and pathological inflammatory scores were significantly different between the control and AEP groups [122±10 and 16.3±1.5 (controls) vs. 71±8.5 and 9.7±1.4 (AEP), respectively; P<0.01]. Thus, the present study revealed that AEP prevents bleomycin-induced acute lung injury in rabbits. PMID:25289037

  10. Dual Oxidase 2 in Lung Epithelia Is Essential for Hyperoxia-Induced Acute Lung Injury in Mice

    PubMed Central

    Kim, Min-Ji; Ryu, Jae-Chan; Kwon, Younghee; Lee, Suhee; Bae, Yun Soo; Yoon, Joo-Heon

    2014-01-01

    Abstract Aims: Acute lung injury (ALI) induced by excessive hyperoxia has been employed as a model of oxidative stress imitating acute respiratory distress syndrome. Under hyperoxic conditions, overloading quantities of reactive oxygen species (ROS) are generated in both lung epithelial and endothelial cells, leading to ALI. Some NADPH oxidase (NOX) family enzymes are responsible for hyperoxia-induced ROS generation in lung epithelial and endothelial cells. However, the molecular mechanisms of ROS production in type II alveolar epithelial cells (AECs) and ALI induced by hyperoxia are poorly understood. Results: In this study, we show that dual oxidase 2 (DUOX2) is a key NOX enzyme that affects hyperoxia-induced ROS production, particularly in type II AECs, leading to lung injury. In DUOX2 mutant mice (DUOX2thyd/thyd) or mice in which DUOX2 expression is knocked down in the lungs, hyperoxia-induced ALI was significantly lower than in wild-type (WT) mice. DUOX2 was mainly expressed in type II AECs, but not endothelial cells, and hyperoxia-induced ROS production was markedly reduced in primary type II AECs isolated from DUOX2thyd/thyd mice. Furthermore, DUOX2-generated ROS are responsible for caspase-mediated cell death, inducing ERK and JNK phophorylation in type II AECs. Innovation: To date, no role for DUOX2 has been defined in hyperoxia-mediated ALI despite it being a NOX homologue and major ROS source in lung epithelium. Conclusion: Here, we present the novel finding that DUOX2-generated ROS induce AEC death, leading to hyperoxia-induced lung injury. Antioxid. Redox Signal. 21, 1803–1818. PMID:24766345

  11. Corticosteroids prevent acute lung dysfunction caused by thoracic irradiation in unanesthetized sheep

    SciTech Connect

    Loyd, J.E.; Bolds, J.M.; Wickersham, N.; Malcolm, A.W.; Brigham, K.L.

    1988-11-01

    We sought to determine the effect of corticosteroid therapy in a new acute model of oxidant lung injury, thoracic irradiation in awake sheep. Sheep were irradiated with 1,500 rads to the whole chest except for blocking the heart and adjacent ventral lung. Seven experimental sheep were given methylprednisolone (1 g intravenously every 6 h for four doses) and thoracic irradiation; control sheep received only irradiation. In irradiated control sheep, lung lymph flow increased from baseline (7.6 ml/h) to peak at 3 h (13.2), and lung lymph protein clearance increased from 5.1 to 9.7 ml/h. Mean pulmonary artery pressure increased in the irradiated control sheep from 19 to 32.4 cm H/sub 2/O, whereas the lung lymph thromboxane concentration increased from 0.09 to 6.51 ng/ml at 3 h. Arterial oxygen tension in irradiated control sheep fell gradually from 86 mm Hg at baseline to 65 mm Hg at 8 h. Methylprednisolone administration significantly prevented the increase in lung lymph protein clearance, mean pulmonary artery pressure, and lung lymph thromboxane concentration. Methylprednisolone also prevented the fall in arterial oxygen tension after thoracic irradiation, but did not prevent a further decrease in lymphocytes in blood or lung lymph after radiation. We conclude that corticosteroid therapy prevents most of the acute physiologic changes caused by thoracic irradiation in awake sheep.

  12. CLOCK modulates survival and acute lung injury in mice with polymicrobial sepsis.

    PubMed

    Wang, Chao-Yung; Hsieh, Ming-Jer; Hsieh, I-Chang; Shie, Shian-Sen; Ho, Ming-Yun; Yeh, Jih-Kai; Tsai, Ming-Lung; Yang, Chia-Hung; Hung, Kuo-Chun; Wang, Chun-Chieh; Wen, Ming-Shien

    2016-09-16

    Polymicrobial sepsis is a potentially fatal condition and a significant burden on health care systems. Acute lung injury is the most common complication of sepsis and results in high mortality. However, there has been no recent significant progress in the treatment of sepsis or acute lung injury induced by sepsis. Here we show that mice deficient in the circadian protein CLOCK had better survival than wild-type mice after induction of polymicrobial sepsis by cecal ligation and puncture. Inflammatory cytokine production was attenuated and bacterial clearance was improved in CLOCK-deficient mice. Moreover, acute lung injury after induction of sepsis was significantly decreased in CLOCK-deficient mice. Genome-wide profiling analysis showed that inhibin signaling was reduced in CLOCK-deficient mice. These data establish the importance of circadian CLOCK-inhibin signaling in sepsis, which may have potential therapeutic implications. PMID:27520377

  13. Renin-angiotensin system and its role in hyperoxic acute lung injury.

    PubMed

    Zhang, P X; Han, C H; Zhou, F J; Li, L; Zhang, H M; Liu, W W

    2016-01-01

    Oxygen is essential to sustain life, but at a high partial pressure oxygen may cause toxicity to the human body. These injuries to the lung are known as hyperoxic acute lung injury [HALI]). To date, numerous studies have been conducted to investigate the pathogenesis of HALI, for which some hypotheses have been proposed. Accumulating evidence indicates that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of some lung diseases, including acute lung injury (ALI), chronic obstructive pulmonary disease (COPD) and HALI. In this review, we briefly introduce the classic RAS, local (tissue) RAS and intracellular RAS, and we summarize findings on the relationship between local/classic RAS and HALI. The importance--and ambiguity--of the results of these studies indicate a need for further investigations of the RAS and its role in the patho- genesis of HALI. PMID:27416692

  14. Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

    PubMed Central

    2012-01-01

    Objective Sulfur mustard (SM) is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980–1988). It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries. Method This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment. Results Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. Conclusion Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments. PMID:23351279

  15. Resolvin D1 protects against inflammation in experimental acute pancreatitis and associated lung injury.

    PubMed

    Liu, Yong; Zhou, Dan; Long, Fei-Wu; Chen, Ke-Ling; Yang, Hong-Wei; Lv, Zhao-Yin; Zhou, Bin; Peng, Zhi-Hai; Sun, Xiao-Feng; Li, Yuan; Zhou, Zong-Guang

    2016-03-01

    Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis. PMID:26702138

  16. Modeling the dynamics of recruitment and derecruitment in mice with acute lung injury.

    PubMed

    Massa, Christopher B; Allen, Gilman B; Bates, Jason H T

    2008-12-01

    Lung recruitment and derecruitment contribute significantly to variations in the elastance of the respiratory system during mechanical ventilation. However, the decreases in elastance that occur with deep inflation are transient, especially in acute lung injury. Bates and Irvin (8) proposed a model of the lung that recreates time-varying changes in elastance as a result of progressive recruitment and derecruitment of lung units. The model is characterized by distributions of critical opening and closing pressures throughout the lung and by distributions of speeds with which the processes of opening and closing take place once the critical pressures have been achieved. In the present study, we adapted this model to represent a mechanically ventilated mouse. We fit the model to data collected in a previous study from control mice and mice in various stages of acid-induced acute lung injury (3). Excellent fits to the data were obtained when the normally distributed critical opening pressures were about 5 cmH(2)O above the closing pressures and when the hyperbolically distributed opening velocities were about an order of magnitude greater than the closing velocities. We also found that, compared with controls, the injured mice had markedly increased opening and closing pressures but no change in the velocities, suggesting that the key biophysical change wrought by acid injury is dysfunction of surface tension at the air-liquid interface. Our computational model of lung recruitment and derecruitment dynamics is thus capable of accurately mimicking data from mice with acute lung injury and may provide insight into the altered biophysics of the injured lung. PMID:18948446

  17. 17β-estradiol protects the lung against acute injury: possible mediation by vasoactive intestinal polypeptide.

    PubMed

    Hamidi, Sayyed A; Dickman, Kathleen G; Berisha, Hasan; Said, Sami I

    2011-12-01

    Beyond their classical role as a class of female sex hormones, estrogens (e.g. 17β-estradiol) exert important biological actions, both protective and undesirable. We have investigated the ability of estradiol to protect the lung in three models of acute injury induced by 1) oxidant stress due to the herbicide paraquat; 2) excitotoxicity, caused by glutamate agonist N-methyl-d-aspartate; and 3) acute alveolar anoxia. We also assessed the role of estrogen receptors (ER) ERα and ERβ and the neuropeptide vasoactive intestinal peptide (VIP) in mediating this protection. Isolated guinea pig or rat lungs were perfused in situ at constant flow and mechanically ventilated. The onset and severity of lung injury were monitored by increases in pulmonary arterial and airway pressures, wet/dry lung weight ratio, and bronchoalveolar lavage fluid protein content. Estradiol was infused into the pulmonary circulation, beginning 10 min before induction of injury and continued for 60-90 min. Lung injury was marked by significant increases in the above measurements, with paraquat producing the most severe, and excitotoxicity the least severe, injury. Estradiol significantly attenuated the injury in each model. Both ER were constitutively expressed and immunohistochemically demonstrable in normal lung, and their selective agonists reduced anoxic injury, the only model in which they were tested. As it protected against injury, estradiol rapidly and significantly stimulated VIP mRNA expression in rat lung. Estradiol attenuated acute lung injury in three experimental models while stimulating VIP gene expression, a known mechanism of lung protection. The up-regulated VIP expression could have partially mediated the protection by estrogen. PMID:22009726

  18. 17β-Estradiol Protects the Lung against Acute Injury: Possible Mediation by Vasoactive Intestinal Polypeptide

    PubMed Central

    Hamidi, Sayyed A.; Dickman, Kathleen G.; Berisha, Hasan

    2011-01-01

    Beyond their classical role as a class of female sex hormones, estrogens (e.g. 17β-estradiol) exert important biological actions, both protective and undesirable. We have investigated the ability of estradiol to protect the lung in three models of acute injury induced by 1) oxidant stress due to the herbicide paraquat; 2) excitotoxicity, caused by glutamate agonist N-methyl-d-aspartate; and 3) acute alveolar anoxia. We also assessed the role of estrogen receptors (ER) ERα and ERβ and the neuropeptide vasoactive intestinal peptide (VIP) in mediating this protection. Isolated guinea pig or rat lungs were perfused in situ at constant flow and mechanically ventilated. The onset and severity of lung injury were monitored by increases in pulmonary arterial and airway pressures, wet/dry lung weight ratio, and bronchoalveolar lavage fluid protein content. Estradiol was infused into the pulmonary circulation, beginning 10 min before induction of injury and continued for 60–90 min. Lung injury was marked by significant increases in the above measurements, with paraquat producing the most severe, and excitotoxicity the least severe, injury. Estradiol significantly attenuated the injury in each model. Both ER were constitutively expressed and immunohistochemically demonstrable in normal lung, and their selective agonists reduced anoxic injury, the only model in which they were tested. As it protected against injury, estradiol rapidly and significantly stimulated VIP mRNA expression in rat lung. Estradiol attenuated acute lung injury in three experimental models while stimulating VIP gene expression, a known mechanism of lung protection. The up-regulated VIP expression could have partially mediated the protection by estrogen. PMID:22009726

  19. Pathogenesis of acute and chronic lung injury induced by foreign compounds

    SciTech Connect

    Witschi, H.P.; Lindenschmidt, R.C.

    1984-01-01

    The lung may become damaged by both airborne or bloodborne agents. Mechanisms implicated in the pathogenesis of lung injury include formation of highly reactive metabolites formed by pulmonary mixed function oxidases or formation of free oxygen radicals. Acute and chronic damage can be evaluated by several methods, such as histology and quantitative morphometry, non-invasive and non-destructive respiratory function tests, and with biochemical techniques that include measuring lavage enzyme levels or quantitating the presence of macromolecules such as collagen. In addition, cell kinetics provide an additional method to explore events following lung damage. 34 references.

  20. The pathology of the acute and chronic stages of farmer's lung

    PubMed Central

    Seal, R. M. E.; Hapke, E. J.; Thomas, G. O.; Meek, J. C.; Hayes, M.

    1968-01-01

    The pathology of five patients who had a biopsy in the acute stage is described; interstitial pneumonia, sarcoid-like granulomata, bronchiolitis, and vasculitis were found. Three of these patients progressed to the chronic stage, when the one with the most extensive bronchiolar involvement had lung function findings of airway obstruction. One progressed to the chronic stage with lung function findings of a transfer defect, and another had radiographic evidence of pulmonary fibrosis with normal lung function tests at rest. The pathology of the chronic stage is described in six patients, with necropsy findings in five. Interstitial pulmonary fibrosis, cystic change, and pulmonary hypertensive changes were the principal findings. Images PMID:5680234

  1. A decremental PEEP trial for determining open-lung PEEP in a rabbit model of acute lung injury.

    PubMed

    Hua, Yi-Ming; Lien, Shao-Hung; Liu, Tao-Yuan; Lee, Chuen-Ming; Yuh, Yeong-Seng

    2008-04-01

    A positive end-expiratory pressure (PEEP) above the lower inflection point (LIP) of the pressure-volume curve has been thought necessary to maintain recruited lung volume in acute lung injury (ALI). We used a strategy to identify the level of open-lung PEEP (OLP) by detecting the maximum tidal compliance during a decremental PEEP trial (DPT). We performed a randomized controlled study to compare the effect of the OLP to PEEP above LIP and zero PEEP on pulmonary mechanics, gas exchange, hemodynamic change, and lung injury in 26 rabbits with ALI. After recruitment maneuver, the lavage-injured rabbits received DPTs to identify the OLP. Animals were randomized to receive volume controlled ventilation with either: (a) PEEP = 0 cm H2O (ZEEP); (b) PEEP = 2 cm H2O above OLP (OLP + 2); or (c) PEEP = 2 cm H2O above LIP (LIP + 2). Peak inspiratory pressure and mean airway pressure were recorded and arterial blood gases were analyzed every 30 min. Mean blood pressure and heart rate were monitored continuously. Lung injury severity was assessed by lung wet/dry weight ratio. Animals in OLP + 2 group had less lung injury as well as relatively better compliance, more stable pH, and less hypercapnia compared to the LIP + 2 and ZEEP groups. We concluded that setting PEEP according to the OLP identified by DPTs is an effective method to attenuate lung injury. This strategy could be used as an indicator for optimal PEEP. The approach is simple and noninvasive and may be of clinical interest. PMID:18293413

  2. Strong correlation between lung ultrasound and chest computerized tomography imaging for the detection of acute lung injury/acute respiratory distress syndrome in rats

    PubMed Central

    Ma, Huan; Huang, Daozheng; Guo, Liheng; Chen, Quanfu; Zhong, Wenzhao

    2016-01-01

    Background Lung ultrasound (LUS) is a clinical imaging technique for diagnosing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In humans and several large animals, LUS demonstrates similar specificity and sensitivity to computerized tomography (CT) scanning. Current study evaluated the degree of agreement between LUS and CT imaging in characterizing ALI/ARDS in rats. Methods Thirty male Sprague-Dawley rats were imaged by LUS before randomization into three groups to receive intratracheal saline, 3 or 6 mg/kg LPS respectively (n=10). LUS and CT imaging was conducted 2 hours after instillation. Cross table analyses and kappa statistics were used to determine agreement levels between LUS and CT assessments of lung condition. Results Before instillation, rats presented with a largely A-pattern in LUS images, however, a significantly increase B-lines were observed in all groups after instillation and showed dose response to LPS or to saline. One rat treated with 6 mg/kg lipopolysaccharide (LPS) presented with lung consolidation. The agreement between the LUS and the CT in detecting the main characteristics of ALI/ARDS in rat was strong (r=0.758, P<0.01, k=0.737). Conclusions In conclusion, LUS detects ALI/ARDS with high agreement with micro PET/CT scanning in a rat model, suggesting that LUS represents a positive refinement in rat ALI/ARDS disease models. PMID:27499930

  3. Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.

    PubMed

    Gupta, Arjun; Sen, Shiraj; Naina, Harris

    2016-01-01

    Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury. PMID:27053543

  4. Time profile of oxidative stress and neutrophil activation in ovine acute lung injury and sepsis.

    PubMed

    Lange, Matthias; Szabo, Csaba; Traber, Daniel L; Horvath, Eszter; Hamahata, Atsumori; Nakano, Yoshimitsu; Traber, Lillian D; Cox, Robert A; Schmalstieg, Frank C; Herndon, David N; Enkhbaatar, Perenlei

    2012-05-01

    The formation of oxidative stress in the lung and activation of neutrophils are major determinants in the development of respiratory failure after acute lung injury and sepsis. However, the time changes of these pathogenic factors have not been sufficiently described. Twenty-four chronically instrumented sheep were subjected to cotton smoke inhalation injury and instillation of live Pseudomonas aeruginosa into both lungs. The sheep were euthanized at 4, 8, 12, 18, and 24 h after injury. Additional sheep received sham injury and were euthanized after 24 h. Pulmonary function was assessed by determination of oxygenation index and pulmonary shunt fraction. In addition, lung tissue was harvested at the respective time points for the measurement of malondialdehyde, interleukin 6, poly(ADP ribose), myeloperoxidase, and alveolar polymorphonuclear neutrophil score. The injury induced severe respiratory failure that was associated with an early increase in lipid peroxidation and interleukin 6 expression. The injury further led to an increase in poly(ADP ribose) activity that reached its peak at 12 h after injury and declined afterward. In addition, progressive increases in markers of neutrophil accumulation in the lung were observed. The peak of neutrophil accumulation in the lung was associated with a severe depletion of circulating neutrophils. The results from our model may enhance the understanding of the pathophysiological alterations after acute lung injury and sepsis and thus be useful in exploring therapeutic interventions directed at modifying the expression or activation of inflammatory mediators. PMID:22266977

  5. Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury

    PubMed Central

    Tsurumaki, Hiroaki; Mogi, Chihiro; Aoki-Saito, Haruka; Tobo, Masayuki; Kamide, Yosuke; Yatomi, Masakiyo; Sato, Koichi; Dobashi, Kunio; Ishizuka, Tamotsu; Hisada, Takeshi; Yamada, Masanobu; Okajima, Fumikazu

    2015-01-01

    Acute lung injury is characterized by the infiltration of neutrophils into lungs and the subsequent impairment of lung function. Here we explored the role of TDAG8 in lung injury induced by lipopolysaccharide (LPS) administrated intratracheally. In this model, cytokines and chemokines released from resident macrophages are shown to cause neutrophilic inflammation in the lungs. We found that LPS treatment increased TDAG8 expression in the lungs and confirmed its expression in resident macrophages in bronchoalveolar lavage (BAL) fluids. LPS administration remarkably increased neutrophil accumulation without appreciable change in the resident macrophages, which was associated with increased penetration of blood proteins into BAL fluids, interstitial accumulation of inflammatory cells, and damage of the alveolar architecture. The LPS-induced neutrophil accumulation and the associated lung damage were enhanced in TDAG8-deficient mice as compared with those in wild-type mice. LPS also increased several mRNA and protein expressions of inflammatory cytokines and chemokines in the lungs or BAL fluids. Among these inflammatory mediators, mRNA and protein expression of KC (also known as CXCL1), a chemokine of neutrophils, were significantly enhanced by TDAG8 deficiency. We conclude that TDAG8 is a negative regulator for lung neutrophilic inflammation and injury, in part, through the inhibition of chemokine production. PMID:26690120

  6. Signaling through the A2B Adenosine Receptor Dampens Endotoxin-Induced Acute Lung Injury

    PubMed Central

    Schingnitz, Ulrich; Hartman, Katherine; MacManus, Christopher F.; Eckle, Tobias; Zug, Stephanie; Colgan, Sean P.; Eltzschig, Holger K.

    2010-01-01

    Sepsis and septic acute lung injury are among the leading causes for morbidity and mortality of critical illness. Extracellular adenosine is a signaling molecule implicated in the cellular adaptation to hypoxia, ischemia or inflammation. Therefore, we pursued the role of the A2B adenosine receptor (A2BAR) as potential therapeutic target in endotoxin-induced acute lung injury. We gained initial insight from in vitro studies of cultured endothelia or epithelia exposed to inflammatory mediators showing time-dependent induction of the A2BAR (up to 12.9±3.4-fold, p<0.05). Similarly, murine studies of endotoxin-induced lung injury identified an almost 4.6-fold induction of A2BAR transcript and corresponding protein induction with LPS-exposure. Studies utilizing A2BAR promoter constructs and RNA-protection assays indicated that A2BAR induction involved mRNA stability. Functional studies of LPS-induced lung injury revealed that pharmacological inhibition or genetic deletion of the A2BAR was associated with dramatic increases in lung inflammation and histologic tissue injury. Studies of A2BAR-bone marrow chimeric mice suggested pulmonary A2BAR signaling in lung protection. Finally, studies with a specific A2BAR agonist (BAY 60-6583) demonstrated attenuation of lung inflammation and pulmonary edema in wild-type but not in gene-targeted mice for the A2BAR. These studies suggest the A2BAR as potential therapeutic target in the treatment of endotoxin-induced forms of acute lung injury. PMID:20348420

  7. αKlotho deficiency in acute kidney injury contributes to lung damage.

    PubMed

    Ravikumar, Priya; Li, Liping; Ye, Jianfeng; Shi, Mingjun; Taniguchi, Masatomo; Zhang, Jianning; Kuro-O, Makoto; Hu, Ming Chang; Moe, Orson W; Hsia, Connie C W

    2016-04-01

    αKlotho is a circulating protein that originates predominantly from the kidney and exerts cytoprotective effects in distant sites. We previously showed in rodents that the lung is particularly vulnerable to αKlotho deficiency. Because acute lung injury is a common and serious complication of acute kidney injury (AKI), we hypothesized that αKlotho deficiency in AKI contributes to lung injury. To test the hypothesis, we created AKI by renal artery ischemia-reperfusion in rats and observed the development of alveolar interstitial edema and increased pulmonary oxidative damage to DNA, protein, and lipids. Administration of αKlotho-containing conditioned media 6 h post-AKI did not alter plasma creatinine but improved recovery of endogenous αKlotho production 3 days post-AKI, reduced lung edema and oxidative damage, and increased endogenous antioxidative capacity in the lung. Intravenously injected αKlotho rapidly exits alveolar capillaries as a macromolecule, suggesting transcytosis and direct access to the epithelium. To explore the epithelial action of αKlotho, we simulated oxidative stress in vitro by adding hydrogen peroxide to cultured A549 lung epithelial cells. Purified recombinant αKlotho directly protected cells at 20 pM with half-maximal effects at 40-50 pM, which is compatible with circulating αKlotho levels. Addition of recombinant αKlotho activated an antioxidant response element reporter and increased the levels of target proteins of the nuclear factor erythroid-derived 2 related factor system. In summary, αKlotho deficiency in AKI contributes to acute lung injury by reducing endogenous antioxidative capacity and increasing oxidative damage in the lung. αKlotho replacement partially reversed these abnormalities and mitigated pulmonary complications in AKI. PMID:26718784

  8. [Acute respiratory distress syndrome caused by tropical eosinophilic lung disease: a case in Gabon].

    PubMed

    Chani, M; Iken, M; Eljahiri, Y; Nzenze, J R; Mion, G

    2011-04-01

    The purpose of this report is to describe the case of a 28-year-old woman in whom acute respiratory distress syndrome (ARDS) following cholecystectomy led to the discovery of eosinophilic lung disease. Outcome was favorable after oxygenotherapy and medical treatment using ivermectin and corticosteroids. The case shows that hypereosinophilic syndrome can be the underlying cause of ARDS. PMID:21695880

  9. MATRILYSIN PARTICIPATES IN THE ACUTE LUNG INJURY INDUCED BY OIL COMBUSTION PRODUCTS

    EPA Science Inventory

    ROLE OF MATRILYSIN IN THE ACUTE LUNG INJURY INDUCED BY OIL COMBUSTION PARTICLES.

    K L Dreher1, WY Su2 and C L Wilson3. 1US Environmental Protection Agency, Research Triangle Park, NC; 2Duke University, Durham, NC;3Washington University, St. Louis, MO.

    Mechanisms by ...

  10. ROLE OF CELL SIGNALING IN PROTECTION FROM DIESEL AND LPS INDUCED ACUTE LUNG INJURY

    EPA Science Inventory

    We have previously demonstrated in CD-1 mice that pre-administration of N-acetyl cysteine (NAC) or the p38 MAP kinase inhibitor (SB203580) reduces acute lung injury and inflammation following pulmonary exposures to diesel exhaust particles (DEP) or lipopolysaccharide (LPS). Here ...

  11. Clinical course of acute chemical lung injury caused by 3-chloropentafluoropene.

    PubMed

    Morita, Satomu; Takimoto, Takayuki; Kawahara, Kunimitsu; Nishi, Katsuji; lino, Morio

    2013-01-01

    Perfluoroallyl chloride (PFAC), a fluorine-containing compound, has very severe toxicity, but this toxicity is not well characterised. We report a fatal case of acute chemical lung injury caused by the inhalation of PFAC. A 39-year-old man, working at a chemical factory, inhaled PFAC gas and died 16 days later of acute lung injury with severe pneumothorax. We present his clinical course together with thoracic CT findings, autopsy and analysis of PFAC in blood and urine samples with gas chromatograph-mass spectrometry. Previously, a fatal case of PFAC was reported in 1981 but PFAC was not identified in any of the patient's samples. In our patient, we identified PFAC in both blood and urine samples. Our toxicological analysis may be used as a reference to detect PFAC toxicity in the future. Our study should be helpful for diagnosing lung injury induced by a highly toxic gas, such as PFAC. PMID:24311414

  12. The effect of fibreoptic bronchoscopy in acute respiratory distress syndrome: experimental evidence from a lung model.

    PubMed

    Nay, M-A; Mankikian, J; Auvet, A; Dequin, P-F; Guillon, A

    2016-02-01

    Flexible bronchoscopy is essential for appropriate care during mechanical ventilation, but can significantly affect mechanical ventilation of the lungs, particularly for patients with acute respiratory distress syndrome. We aimed to describe the consequences of bronchoscopy during lung-protective ventilation in a bench study, and thereby to determine the optimal diameter of the bronchoscope for avoiding disruption of the protective-ventilation strategy during the procedure. Immediately following the insertion of the bronchoscope into the tracheal tube, either minute ventilation decreased significantly, or positive end-expiratory pressure increased substantially, according to the setting of the inspiratory pressure limit. The increase in end-expiratory pressure led to an equivalent increase in the plateau pressure, and lung-protective ventilation was significantly altered during the procedure. We showed that a bronchoscope with an external diameter of 4 mm (or less) would allow safer bronchoscopic interventions in patients with severe acute respiratory distress syndrome. PMID:26559154

  13. Clinical course of acute chemical lung injury caused by 3-chloropentafluoropene

    PubMed Central

    Morita, Satomu; Takimoto, Takayuki; Kawahara, Kunimitsu; Nishi, Katsuji

    2013-01-01

    Perfluoroallyl chloride (PFAC), a fluorine-containing compound, has very severe toxicity, but this toxicity is not well characterised. We report a fatal case of acute chemical lung injury caused by the inhalation of PFAC. A 39-year-old man, working at a chemical factory, inhaled PFAC gas and died 16 days later of acute lung injury with severe pneumothorax. We present his clinical course together with thoracic CT findings, autopsy and analysis of PFAC in blood and urine samples with gas chromatograph–mass spectrometry. Previously, a fatal case of PFAC was reported in 1981 but PFAC was not identified in any of the patient's samples. In our patient, we identified PFAC in both blood and urine samples. Our toxicological analysis may be used as a reference to detect PFAC toxicity in the future. Our study should be helpful for diagnosing lung injury induced by a highly toxic gas, such as PFAC. PMID:24311414

  14. IMMUNOLOGICAL METHODS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Environmental microbiology does not deal with all aspects of immunology or the immune responses per se, but instead adapts immunology-based research technologies or immunoassays for the study of microorganisms and chemical contaminants in association with the environment. The primary immunologic-bas...

  15. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS

    PubMed Central

    SEPEHR, REYHANEH; AUDI, SAID H.; MALEKI, SEPIDEH; STANISZEWSKI, KEVIN; EIS, ANNIE L.; KONDURI, GIRIJA G.; RANJI, MAHSA

    2014-01-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI) in adults and bronchopulmonary dysplasia (BPD) in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD), referred to as NADH redox ratio (NADH RR) has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS) exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2) pups, hyperoxic (90% O2) pups, pups treated with LPS (normoxic + LPS), and pups treated with LPS and hyperoxia (hyperoxic + LPS). Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure. PMID:24672581

  16. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS.

    PubMed

    Sepehr, Reyhaneh; Audi, Said H; Maleki, Sepideh; Staniszewski, Kevin; Eis, Annie L; Konduri, Girija G; Ranji, Mahsa

    2013-07-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI) in adults and bronchopulmonary dysplasia (BPD) in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD), referred to as NADH redox ratio (NADH RR) has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS) exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2) pups, hyperoxic (90% O2) pups, pups treated with LPS (normoxic + LPS), and pups treated with LPS and hyperoxia (hyperoxic + LPS). Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure. PMID:24672581

  17. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury.

    PubMed

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation. PMID:26617279

  18. Pulmonary administration of a water-soluble curcumin complex reduces severity of acute lung injury.

    PubMed

    Suresh, Madathilparambil V; Wagner, Matthew C; Rosania, Gus R; Stringer, Kathleen A; Min, Kyoung Ah; Risler, Linda; Shen, Danny D; Georges, George E; Reddy, Aravind T; Parkkinen, Jaakko; Reddy, Raju C

    2012-09-01

    Local or systemic inflammation can result in acute lung injury (ALI), and is associated with capillary leakage, reduced lung compliance, and hypoxemia. Curcumin, a plant-derived polyphenolic compound, exhibits potent anti-inflammatory properties, but its poor solubility and limited oral bioavailability reduce its therapeutic potential. A novel curcumin formulation (CDC) was developed by complexing the compound with hydroxypropyl-γ-cyclodextrin (CD). This results in greatly enhanced water solubility and stability that facilitate direct pulmonary delivery. In vitro studies demonstrated that CDC increased curcumin's association with and transport across Calu-3 human airway epithelial cell monolayers, compared with uncomplexed curcumin solubilized using DMSO or ethanol. Importantly, Calu-3 cell monolayer integrity was preserved after CDC exposure, whereas it was disrupted by equivalent uncomplexed curcumin solutions. We then tested whether direct delivery of CDC to the lung would reduce severity of ALI in a murine model. Fluorescence microscopic examination revealed an association of curcumin with cells throughout the lung. The administration of CDC after LPS attenuated multiple markers of inflammation and injury, including pulmonary edema and neutrophils in bronchoalveolar lavage fluid and lung tissue. CDC also reduced oxidant stress in the lungs and activation of the proinflammatory transcription factor NF-κB. These results demonstrate the efficacy of CDC in a murine model of lung inflammation and injury, and support the feasibility of developing a lung-targeted, curcumin-based therapy for the treatment of patients with ALI. PMID:22312018

  19. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  20. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2015-11-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  1. Hypervolemia induces and potentiates lung damage after recruitment maneuver in a model of sepsis-induced acute lung injury

    PubMed Central

    2010-01-01

    Introduction Recruitment maneuvers (RMs) seem to be more effective in extrapulmonary acute lung injury (ALI), caused mainly by sepsis, than in pulmonary ALI. Nevertheless, the maintenance of adequate volemic status is particularly challenging in sepsis. Since the interaction between volemic status and RMs is not well established, we investigated the effects of RMs on lung and distal organs in the presence of hypovolemia, normovolemia, and hypervolemia in a model of extrapulmonary lung injury induced by sepsis. Methods ALI was induced by cecal ligation and puncture surgery in 66 Wistar rats. After 48 h, animals were anesthetized, mechanically ventilated and randomly assigned to 3 volemic status (n = 22/group): 1) hypovolemia induced by blood drainage at mean arterial pressure (MAP)≈70 mmHg; 2) normovolemia (MAP≈100 mmHg), and 3) hypervolemia with colloid administration to achieve a MAP≈130 mmHg. In each group, animals were further randomized to be recruited (CPAP = 40 cm H2O for 40 s) or not (NR) (n = 11/group), followed by 1 h of protective mechanical ventilation. Echocardiography, arterial blood gases, static lung elastance (Est,L), histology (light and electron microscopy), lung wet-to-dry (W/D) ratio, interleukin (IL)-6, IL-1β, caspase-3, type III procollagen (PCIII), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions in lung tissue, as well as lung and distal organ epithelial cell apoptosis were analyzed. Results We observed that: 1) hypervolemia increased lung W/D ratio with impairment of oxygenation and Est,L, and was associated with alveolar and endothelial cell damage and increased IL-6, VCAM-1, and ICAM-1 mRNA expressions; and 2) RM reduced alveolar collapse independent of volemic status. In hypervolemic animals, RM improved oxygenation above the levels observed with the use of positive-end expiratory pressure (PEEP), but increased lung injury and led to higher inflammatory and fibrogenetic

  2. Modifications of lung clearance mechanisms by acute influenza A infection

    SciTech Connect

    Levandowski, R.A.; Gerrity, T.R.; Garrard, C.S.

    1985-10-01

    Four volunteers with naturally acquired, culture-proved influenza A infection inhaled a radiolabeled aerosol to permit investigation of lung mucociliary clearance mechanisms during and after symptomatic illness. Mucus transport in the trachea was undetectable when monitored with an external multidetector probe within 48 hours of the onset of the illness, but was found at a normal velocity by 1 week in three of the four subjects. In two volunteers who coughed 23 to 48 times during the 4.5-hour observation period, whole lung clearance was as fast within the first 48 hours of illness as during health 3 months later in spite of the absence of measurable tracheal mucus transport. Conversely, in spite of the return 1 week later of mucus transport at velocities expected in the trachea, whole lung clearance for the 4.5-hour period was slowed in two volunteers who coughed less than once an hour. The data offer evidence that cough is important in maintaining lung clearance for at least several days after symptomatic influenza A infection when other mechanisms that depend on ciliary function are severely deficient.

  3. Cell-free hemoglobin: a novel mediator of acute lung injury.

    PubMed

    Shaver, Ciara M; Upchurch, Cameron P; Janz, David R; Grove, Brandon S; Putz, Nathan D; Wickersham, Nancy E; Dikalov, Sergey I; Ware, Lorraine B; Bastarache, Julie A

    2016-03-15

    Patients with the acute respiratory distress syndrome (ARDS) have elevated levels of cell-free hemoglobin (CFH) in the air space, but the contribution of CFH to the pathogenesis of acute lung injury is unknown. In the present study, we demonstrate that levels of CFH in the air space correlate with measures of alveolar-capillary barrier dysfunction in humans with ARDS (r = 0.89, P < 0.001) and in mice with ventilator-induced acute lung injury (r = 0.89, P < 0.001). To investigate the specific contribution of CFH to ARDS, we studied the impact of purified CFH in the mouse lung and on cultured mouse lung epithelial (MLE-12) cells. Intratracheal delivery of CFH in mice causes acute lung injury with air space inflammation and alveolar-capillary barrier disruption. Similarly, in MLE-12 cells, CFH increases proinflammatory cytokine expression and increases paracellular permeability as measured by electrical cell-substrate impedance sensing. Next, to determine whether these effects are mediated by the iron-containing heme moiety of CFH, we treated mice with intratracheal hemin, the chloride salt of heme, and found that hemin was sufficient to increase alveolar permeability but failed to induce proinflammatory cytokine expression or epithelial cell injury. Together, these data identify CFH in the air space as a previously unrecognized driver of lung epithelial injury in human and experimental ARDS and suggest that CFH and hemin may contribute to ARDS through different mechanisms. Interventions targeting CFH and heme in the air space could provide a new therapeutic approach for ARDS. PMID:26773065

  4. ROLE OF TACHYKININS IN OZONE-INDUCED ACUTE LUNG INJURY

    EPA Science Inventory

    To examine the hypothesis that the acute, reversible changes caused by O3 exposure are mediated by techykinin release, guinea pigs were depleted of tachykinins using repeated capsaicin (CAP) injections prior to O3 exposure, in an attempt to prevent O3-induced functional changes. ...

  5. Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

    SciTech Connect

    Yoo, Seong Ho; Abdelmegeed, Mohamed A.; Song, Byoung-Joon

    2013-07-05

    Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI.

  6. Ventilator-Induced Lung Injury (VILI) in Acute Respiratory Distress Syndrome (ARDS): Volutrauma and Molecular Effects

    PubMed Central

    Carrasco Loza, R; Villamizar Rodríguez, G; Medel Fernández, N

    2015-01-01

    Acute Respiratory Distress Syndrome (ARDS) is a clinical condition secondary to a variety of insults leading to a severe acute respiratory failure and high mortality in critically ill patients. Patients with ARDS generally require mechanical ventilation, which is another important factor that may increase the ALI (acute lung injury) by a series of pathophysiological mechanisms, whose common element is the initial volutrauma in the alveolar units, and forming part of an entity known clinically as ventilator-induced lung injury (VILI). Injured lungs can be partially protected by optimal settings and ventilation modes, using low tidal volume (VT) values and high positive-end expiratory pressure (PEEP). The benefits in ARDS outcomes caused by these interventions have been confirmed by several prospective randomized controlled trials (RCTs) and are attributed to reduction in volutrauma. The purpose of this article is to present an approach to VILI pathophysiology focused on the effects of volutrauma that lead to lung injury and the ‘mechanotransduction’ mechanism. A more complete understanding about the molecular effects that physical forces could have, is essential for a better assessment of existing strategies as well as the development of new therapeutic strategies to reduce the damage resulting from VILI, and thereby contribute to reducing mortality in ARDS. PMID:26312103

  7. Acute stress reduces intraparenchymal lung natural killer cells via beta-adrenergic stimulation

    PubMed Central

    Kanemi, O; Zhang, X; Sakamoto, Y; Ebina, M; Nagatomi, R

    2005-01-01

    There are lines of evidence that natural killer (NK) cells are sensitive to physical and psychological stress. Alterations in the immune system including NK cells are known to differ among tissues and organs. The effect of stress on the lung immune system, however, has not been well documented in spite of the fact that the lungs always confront viral or bacterial attacks as well as tumour cell metastasis. In this study, we intended to investigate the effect of restraint stress on lung lymphocytes including NK cells. C57BL/6 mice were exposed to 2 h restraint stress. The concentration of plasma epinephrine significantly rose immediately after the release from restraint as compared to home-cage control mice. Flow cytometric analysis revealed that the numbers of most lymphocyte subsets including NK cells were decreased in the lungs and blood but not in the spleen, immediately after restraint stress. Immunohistochemical examination revealed that the number of NK cells was decreased in the intraparenchymal region of the lungs, while the number of alveolar macrophages did not change. The decrease in the number of NK cells in the lungs and blood was reversed by the administration of propranolol, a nonselective beta adrenergic antagonist. Taken together, our findings suggest that acute stress reduces the number of intraparenchymal lung NK cells via activation of beta adrenergic receptors. PMID:15606610

  8. [Current approaches to the treatment of severe hypoxic respiratory insufficiency (acute lung injury; acute respiratory distress syndrome)].

    PubMed

    Kluge, S; Müller, T; Pfeifer, M

    2011-02-01

    Lung-protective ventilation with a low tidal volume, plateau pressure < 30 cm H(2)O. oxygen saturation > 90% and permissive hypercapnia results in reduction of the mortality rate in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The level of the positive end-expiratory pressure (PEEP) must be chosen in relation to oxygen requirement. High frequency oscillatory ventilation and neurally adjusted ventilatory assist are promising methods. However, further studies with firm end-points have to be awaited before a final judgment is possible. Veno-venous extracorporeal membrane oxygenation (ECMO) can ensure life-sustaining gas exchange in patients with severe vitally compromised pulmonary failure, to provide time for lung tissue to heal and reduce ventilatory stress. The latest guidelines for analgesia and sedation in intensive care medicine demand consistent monitoring of the level of sedation and the intensity of pain. The sedation should be interrupted daily, with phases of awakenings and, if possible, spontaneous breathing. Methods of supportive treatment: Positional treatment (prone position) and inhalation of vasodilators can improve ventilation/perfusion mismatch and thus oxygenation. However, administration of surfactant is currently not advised in adult respiratory failure. PMID:21271478

  9. Role of macrophage chemoattractant protein-1 in acute inflammation after lung contusion.

    PubMed

    Suresh, Madathilparambil V; Yu, Bi; Machado-Aranda, David; Bender, Matthew D; Ochoa-Frongia, Laura; Helinski, Jadwiga D; Davidson, Bruce A; Knight, Paul R; Hogaboam, Cory M; Moore, Bethany B; Raghavendran, Krishnan

    2012-06-01

    Lung contusion (LC), commonly observed in patients with thoracic trauma is a leading risk factor for development of acute lung injury/acute respiratory distress syndrome. Previously, we have shown that CC chemokine ligand (CCL)-2, a monotactic chemokine abundant in the lungs, is significantly elevated in LC. This study investigated the nature of protection afforded by CCL-2 in acute lung injury/acute respiratory distress syndrome during LC, using rats and CC chemokine receptor (CCR) 2 knockout (CCR2(-/-)) mice. Rats injected with a polyclonal antibody to CCL-2 showed higher levels of albumin and IL-6 in the bronchoalveolar lavage and myeloperoxidase in the lung tissue after LC. Closed-chest bilateral LC demonstrated CCL-2 localization in alveolar macrophages (AMs) and epithelial cells. Subsequent experiments performed using a murine model of LC showed that the extent of injury, assessed by pulmonary compliance and albumin levels in the bronchoalveolar lavage, was higher in the CCR2(-/-) mice when compared with the wild-type (WT) mice. We also found increased release of IL-1β, IL-6, macrophage inflammatory protein-1, and keratinocyte chemoattractant, lower recruitment of AMs, and higher neutrophil infiltration and phagocytic activity in CCR2(-/-) mice at 24 hours. However, impaired phagocytic activity was observed at 48 hours compared with the WT. Production of CCL-2 and macrophage chemoattractant protein-5 was increased in the absence of CCR2, thus suggesting a negative feedback mechanism of regulation. Isolated AMs in the CCR2(-/-) mice showed a predominant M1 phenotype compared with the predominant M2 phenotype in WT mice. Taken together, the above results show that CCL-2 is functionally important in the down-modulation of injury and inflammation in LC. PMID:22281985

  10. Melatonin reduces acute lung inflammation, edema, and hemorrhage in heatstroke rats

    PubMed Central

    Wu, Wen-shiann; Chou, Ming-ting; Chao, Chien-ming; Chang, Chen-kuei; Lin, Mao-tsun; Chang, Ching-ping

    2012-01-01

    Aim: To assess the therapeutic effect of melatonin on heat-induced acute lung inflammation and injury in rats. Methods: Heatstroke was induced by exposing anesthetized rats to heat stress (36 °C, 100 min). Rats were treated with vehicle or melatonin (0.2, 1, 5 mg/kg) by intravenous administration 100 min after the initiatioin of heatstroke and were allowed to recover at room temperature (26 °C). The acute lung injury was quantified by morphological examination and by determination of the volume of pleural exudates, the number of polymorphonuclear (PMN) cells, and the myeloperoxidase (MPO) activity. The concentrations of tumor necrosis factor, interleukin (IL)-1β, IL-6, and IL-10 in bronchoalveolar fluid (BALF) were measured by ELISA. Nitric oxide (NO) level was determined by Griess method. The levels of glutamate and lactate-to-pyruvate ratio were analyzed by CMA600 microdialysis analyzer. The concentrations of hydroxyl radicals were measured by a procedure based on the hydroxylation of sodium salicylates leading to the production of 2,3-dihydroxybenzoic acid (DHBA). Results: Melatonin (1 and 5 mg/kg) significantly (i) prolonged the survival time of heartstroke rats (117 and 186 min vs 59 min); (ii) attenuated heatstroke-induced hyperthermia and hypotension; (iii) attenuated acute lung injury, including edema, neutrophil infiltration, and hemorrhage scores; (iv) down-regulated exudate volume, BALF PMN cell number, and MPO activity; (v) decreased the BALF levels of lung inflammation response cytokines like TNF-alpha, interleukin (IL)-1β, and IL-6 but further increased the level of an anti-inflammatory cytokine IL-10; (vi) reduced BALF levels of glutamate, lactate-to-pyruvate ratio, NO, 2,3-DHBA, and lactate dehydrogenase. Conclusion: Melatonin may improve the outcome of heatstroke in rats by attenuating acute lung inflammation and injury. PMID:22609835

  11. Lung protective ventilation strategies: have we applied them in trauma patients at risk for acute lung injury and acute respiratory distress syndrome?

    PubMed

    Gillis, Robert C; Weireter, Leonard J; Britt, Rebecca C; Cole, Frederic J; Collins, Jay N; Britt, L D

    2007-04-01

    Lung protective ventilation strategies for patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are well documented, and many medical centers fail to apply these strategies in ALI/ARDS. The objective of this study was to determine if we apply these strategies in trauma patients at risk for ALI/ARDS. We undertook a retrospective review of trauma patients mechanically ventilated for > or = 4 days with an ICD-9 for traumatic pneumothorax, hemothorax, lung contusion, and/or fractured ribs admitted from May 1, 1999 through April 30, 2000 (Group 1), the pre-ARDS Network study, and from May 1, 2003 through April 30, 2004 (Group 2), the post-ARDS Network study. Tidal volume (VT)/kg admission body weight, VT/kg ideal body weight (IBW), and plateau and peak pressures were analyzed with respect to mortality. VT/Kg admission body weight and IBW were significantly reduced when comparing Group 1 with Group 2 (9.27 to 8.03 and 11.67 to 10.04, respectively). VT/kg IBW was greater (P < 0.01) for patients who died in Group 1 (13.81) compared with patients who lived (10.29) or died (9.89) in Group 2. Peak and plateau pressures were greater (P < 0.01) in patients who died in Group 1 than patients who lived or died in Group 2. A strict ARDS Network ventilation strategy (VT < 6 mL/kg) is not followed, rather a low plateau/peak pressure strategy is used, which is a form of lung protective ventilation. PMID:17439026

  12. The therapeutic effects of tuberostemonine against cigarette smoke-induced acute lung inflammation in mice.

    PubMed

    Jung, Kyung-Hwa; Beak, Hyunjung; Park, Soojin; Shin, Dasom; Jung, Jaehoon; Park, Sangwon; Kim, Jinju; Bae, Hyunsu

    2016-03-01

    Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking and is characterized by the destruction of lung parenchyma, structural alterations of the small airways, and systemic inflammation. Tuberostemonine (TS) is an alkaloid-type phytochemical from Stemona tuberosa. In the present study, we evaluated the anti-inflammatory effect of TS in a cigarette smoke (CS)-induced mouse model of acute lung inflammation. The mice were whole-body exposed to CS or fresh air for 7 days. TS was administered by an intraperitoneal (i.p.) injection 1h before exposure to CS. To test the effects of TS, the numbers of total cells, neutrophils, macrophages and lymphocytes in the bronchoalveolar lavage (BAL) fluid were counted. Furthermore, we measured the levels of several chemokines, such as GCP-2, MIP-3α, MCP-1 and KC, in the lung tissue. The cellular profiles and histopathological analysis demonstrated that the infiltration of peribronchial and perivascular inflammatory cells significantly decreased in the TS-treated groups compared with the CS-exposure group. The TS treatment significantly ameliorated the airway epithelial thickness induced by CS exposure and caused a significant decrement in the production of chemokines in the lung. These results suggest that TS has anti-inflammatory effects against CS-induced acute lung inflammation. PMID:26849941

  13. Gadolinium chloride attenuates sepsis-induced pulmonary apoptosis and acute lung injury.

    PubMed

    Kishta, Osama A; Goldberg, Peter; Husain, Sabah N A

    2012-01-01

    Gadolinium chloride (GdCl3), a Kupffer cells inhibitor, attenuates acute lung injury; however, the mechanisms behind this effect are not completely elucidated. We tested the hypothesis that GdCl3 acts through the inhibition of lung parenchymal cellular apoptosis. Two groups of rats were injected intraperitoneally with saline or E. coli lipopolysaccharide. In two additional groups, rats were injected with GdCl3 24 hrs prior to saline or LPS administration. At 12 hrs, lung injury, inflammation, and apoptosis were studied. Lung water content, myeloperoxidase activity, pulmonary apoptosis and mRNA levels of interleukin-1 β , -2, -5, -6, -10 and TNF- α rose significantly in LPS-injected animals. Pretreatment with GdCl3 significantly reduced LPS-induced elevation of pulmonary water content, myeloperoxidase activity, cleaved caspase-3 intensity, and attenuated pulmonary TUNEL-positive cells. GdCl3 pre-treatment upregulated IL-1 β , -2 and -10 pulmonary gene expression without significantly affecting the others. These results suggest that GdCl3 attenuates acute lung injury through its effects on pulmonary parenchymal apoptosis. PMID:24049647

  14. Excessive Neutrophils and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza Pneumonitis

    PubMed Central

    Narasaraju, Teluguakula; Yang, Edwin; Samy, Ramar Perumal; Ng, Huey Hian; Poh, Wee Peng; Liew, Audrey-Ann; Phoon, Meng Chee; van Rooijen, Nico; Chow, Vincent T.

    2011-01-01

    Complications of acute respiratory distress syndrome (ARDS) are common among critically ill patients infected with highly pathogenic influenza viruses. Macrophages and neutrophils constitute the majority of cells recruited into infected lungs, and are associated with immunopathology in influenza pneumonia. We examined pathological manifestations in models of macrophage- or neutrophil-depleted mice challenged with sublethal doses of influenza A virus H1N1 strain PR8. Infected mice depleted of macrophages displayed excessive neutrophilic infiltration, alveolar damage, and increased viral load, later progressing into ARDS-like pathological signs with diffuse alveolar damage, pulmonary edema, hemorrhage, and hypoxemia. In contrast, neutrophil-depleted animals showed mild pathology in lungs. The brochoalveolar lavage fluid of infected macrophage-depleted mice exhibited elevated protein content, T1-α, thrombomodulin, matrix metalloproteinase-9, and myeloperoxidase activities indicating augmented alveolar-capillary damage, compared to neutrophil-depleted animals. We provide evidence for the formation of neutrophil extracellular traps (NETs), entangled with alveoli in areas of tissue injury, suggesting their potential link with lung damage. When co-incubated with infected alveolar epithelial cells in vitro, neutrophils from infected lungs strongly induced NETs generation, and augmented endothelial damage. NETs induction was abrogated by anti-myeloperoxidase antibody and an inhibitor of superoxide dismutase, thus implying that NETs generation is induced by redox enzymes in influenza pneumonia. These findings support the pathogenic effects of excessive neutrophils in acute lung injury of influenza pneumonia by instigating alveolar-capillary damage. PMID:21703402

  15. Protective effect of catalpol on lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Fu, Kai; Piao, Taikui; Wang, Mingzhi; Zhang, Jian; Jiang, Jiuyang; Wang, Xuefeng; Liu, Hongyu

    2014-12-01

    Catalpol, an iridiod glucoside isolated from Rehmannia glutinosa, has been reported to have anti-inflammatory properties. Although anti-inflammatory activity of catalpol already reported, its involvement in lung protection has not been reported. Thus, we investigated the role of catalpol on lipopolysaccharide (LPS)-induced acute lung injury in this study. Mice acute lung injury model was induced by intranasal instillation of LPS. Catalpol was administrated 1h prior to or after LPS exposure. The severity of pulmonary injury was evaluated 12h after LPS administration. The results showed that catalpol inhibited lung W/D ratio, myeloperoxidase activity of lung samples, the amounts of inflammatory cells and TNF-α, IL-6, IL-4 and IL-1β in BALF induced by LPS. The production of IL-10 in BALF was up-regulated by catalpol. In vitro, catalpol inhibited TNF-α, IL-6, IL-4 and IL-1β production and up-regulated IL-10 expression in LPS-stimulated alveolar macrophages. Moreover, western blot analysis showed that the activation of NF-κB and MAPK signaling pathways was inhibited by catalpol. Furthermore, catalpol was found to inhibit TLR4 expression induced by LPS. In conclusion, catalpol potently protected against LPS-induced ALI. The protective effect may attribute to the inhibition of TLR4-mediated NF-κB and MAPK signaling pathways. PMID:25063711

  16. Protective effect of U74500A on phorbol myristate acetate-induced acute lung injury.

    PubMed

    Chu, Shi-Jye; Chang, Deh-Ming; Wang, David; Lin, Hen-I; Lin, Shih-Hua; Hsu, Kang

    2004-08-01

    1. The present study was designed to determine whether U74500A could ameliorate acute lung injury (ALI) induced by phorbol myristate acetate (PMA) in our rat isolated lung model compared with any amelioration induced by dimethylthiourea (DMTU), superoxide dismutase (SOD) and catalase. 2. Acute lung injury was induced successfully by PMA during 60 min of observation. At 2 microg/kg, PMA elicited a significant increase in microvascular permeability (measured using the capillary filtration coefficient Kfc), lung weight gain, the lung weight/bodyweight ratio, pulmonary arterial pressure and protein concentration of the bronchoalveolar lavage fluid. 3. Pretreatment with 1.5 mg/kg U74500A significantly attenuated ALI; there was no significant increase in any parameters measured, except for pulmonary arterial pressure. The protective effect of U74500A was approximately the same as that of 600 mg/kg DMTU. However, 6000 U/kg SOD, 50,000 U/kg catalase and 6000 U/kg SOD + 50,000 U/kg catalase had no protective effect. 4. These experimental data suggest that U74500A significantly ameliorates ALI induced by PMA in rats. PMID:15298545

  17. Translational toxicological research: investigating and preventing acute lung injury in organophosphorus insecticide poisoning.

    PubMed

    Hulse, Elspeth J; Clutton, R E; Drummond, G; Eddleston, M

    2014-06-01

    Poisoning through ingestion of organophosphorus (OP) insecticide is a leading cause of suicide globally. Severe poisoning with OP compounds creates an unconscious, paralysed patient with respiratory failure. These symptoms make pulmonary aspiration of stomach contents highly likely, potentially causing an acute lung injury. To explore this hypothesis, we created a Gottingen minipig pulmonary aspiration model (n=26) to investigate the mechanism and severity of lung injury created through pulmonary instillation of 0.5 mL/kg mixtures of porcine gastric juice (GJ), OP and/or its solvent. Early results show that aspiration of OP and GJ causes pulmonary neutrophil sequestration, alveolar haemorrhage and interstitial oedema, with disruption of the alveolar-capillary membrane. Further measurements will include quantitative CT imaging, histopathology scoring, acute lung injury biomarkers and respiratory function. In order to test the validity of the minipig model, a pilot study in Sri Lanka has been devised to observe signs of lung injury in human patients who have ingested OP insecticide with or without clinical evidence of pulmonary aspiration. Lung injury will be assessed with PaO2/FIO2 ratios and physiological dead space measurement. Blood, bronchoalveolar lavage and urine will be taken at 24 and 48 h after poisoning and at 3-4 h in surgical control patients to measure acute lung injury biomarkers. An unpublished toxicology study from Sri Lanka, 2011-2012, showed that over 40% of unconscious poisoned patients with a GCS <9 were not intubated for ambulance transfer between rural and district hospitals. Delay in intubation leads to aspiration pneumonitis and pneumonia in 38%-45% of unconscious poisoned patients. We hypothesise that non-drug assisted placement of supraglottic airways may be a good tool for use in unconscious poisoned patients requiring transfer from small rural hospitals in Asia. They could confer better airway protection than no airway intervention

  18. Efficacy and safety of mesenchymal stromal cells in preclinical models of acute lung injury: a systematic review protocol

    PubMed Central

    2014-01-01

    Background Acute respiratory distress syndrome (ARDS) in humans is caused by an unchecked proinflammatory response that results in diffuse and severe lung injury, and it is associated with a mortality rate of 35 to 45%. Mesenchymal stromal cells (MSCs; ‘adult stem cells’) could represent a promising new therapy for this syndrome, since preclinical evidence suggests that MSCs may ameliorate lung injury. Prior to a human clinical trial, our aim is to conduct a systematic review to compare the efficacy and safety of MSC therapy versus controls in preclinical models of acute lung injury that mimic some aspects of the human ARDS. Methods/Design We will include comparative preclinical studies (randomized and non-randomized) of acute lung injury in which MSCs were administered and outcomes compared to animals given a vehicle control. The primary outcome will be death. Secondary outcomes will include the four key features of preclinical acute lung injury as defined by the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar capillary barrier, lung inflammatory response, and physiological dysfunction) and pathogen clearance for acute lung injury models that are caused by infection. Electronic searches of MEDLINE, Embase, BIOSIS Previews, and Web of Science will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the Cochrane risk of bias tool, and individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Discussion The results of this systematic review will comprehensively summarize the safety and efficacy of MSC therapy in preclinical models of acute lung injury. Our results will help translational scientists and

  19. Mechanisms of Indirect Acute Lung Injury: A Novel Role for the Co-Inhibitory Receptor, Programmed Death-1 (PD-1)

    PubMed Central

    Monaghan, Sean F.; Thakkar, Rajan K.; Heffernan, Daithi S.; Huang, Xin; Chung, Chun-Shiang; Lomas-Neira, Joanne; Cioffi, William G.; Ayala, Alfred

    2011-01-01

    Objective To determine the contribution of PD-1 in the morbidity and mortality associated with the development of indirect-acute lung injury Summary Background Data The immune cell interaction(s) leading to indirect-acute lung injury are not completely understood. In this respect, while we have recently shown that the murine cell surface co-inhibitory receptor, Programmed Cell death receptor (PD)-1, has a role in septic morbidity/mortality that is mediated in part through the effects on the innate immune arm. However, it is not know if PD-1 has a role in the development of indirect-acute lung injury and how this may be mediated at a cellular level. Methods PD-1 −/− mice were used in a murine model of indirect-acute lung injury (hemorrhagic shock followed 24 h after with cecal ligation & puncture-septic challenge) and compared to wild type controls. Groups were initially compared for survival and subsequently for markers of pulmonary inflammation, influx of lymphocytes and neutrophils, and expression of PD-1 and its ligand, PD-L1. In addition, peripheral blood leukocytes of patients with indirect-acute lung injury were examined to assess changes in cellular PD-1 expression relative to mortality. Results PD-1 −/− mice showed improved survival compared to wild type controls. In the mouse lung, CD4+, CD11c+ and Gr-1+ cells showed increased PD-1 expression in response to indirect-acute lung injury. However, while the rise in BAL fluid protein concentrations, lung IL-6, and lung MCP-1 were similar between PD-1 −/− and wild type animals subjected to indirect acute lung injury, the PD-1 −/− animals that were subjected to shock/septic challenge had reduced CD4:CD8 ratios, TNF-α levels, MPO activity, and caspase 3 levels in the lung. Comparatively, we observed that humans, who survived their acute lung injury, had significantly lower expression of PD-1 on T cells. Conclusions PD-1 expression contributes to mortality following the induction of indirect-acute

  20. Calcitriol inhibits tumor necrosis factor alpha and macrophage inflammatory protein-2 during lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Tan, Zhu-Xia; Chen, Yuan-Hua; Xu, Shen; Qin, Hou-Ying; Wang, Hua; Zhang, Cheng; Xu, De-Xiang; Zhao, Hui

    2016-08-01

    Acute lung injury is a common complication of sepsis in intensive care unit patients with an extremely high mortality. The present study investigated the effects of calcitriol, the active form of vitamin D, on tumor necrosis factor alpha (TNF-α) and macrophage inflammatory protein-2 (MIP-2) in sepsis-induced acute lung injury. Mice were intraperitoneally (i.p.) injected with lipopolysaccharide (LPS, 1.0mg/kg) to establish the animal model of sepsis-induced acute lung injury. Some mice were i.p. injected with calcitriol (1.0μg/kg) before LPS injection. An obvious infiltration of inflammatory cells in the lungs was observed beginning at 1h after LPS injection. Correspondingly, TNF-α and MIP-2 in sera and lung homogenates were markedly elevated in LPS-treated mice. Interestingly, calcitriol obviously alleviated LPS-induced infiltration of inflammatory cells in the lungs. Moreover, calcitriol markedly attenuated LPS-induced elevation of TNF-α and MIP-2 in sera and lung homogenates. Further analysis showed that calcitriol repressed LPS-induced p38 mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) phosphorylation. In addition, calcitriol blocked LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65 and p50 subunit in the lungs. Taken together, these results suggest that calcitriol inhibits inflammatory cytokines production in LPS-induced acute lung injury. PMID:27216047

  1. Cigarette Smoke Disrupted Lung Endothelial Barrier Integrity and Increased Susceptibility to Acute Lung Injury via Histone Deacetylase 6.

    PubMed

    Borgas, Diana; Chambers, Eboni; Newton, Julie; Ko, Junsuk; Rivera, Stephanie; Rounds, Sharon; Lu, Qing

    2016-05-01

    Epidemiologic evidence indicates that cigarette smoke (CS) is associated with the development of acute lung injury (ALI). We have previously shown that brief CS exposure exacerbates lipopolysaccharide (LPS)-induced ALI in vivo and endothelial barrier dysfunction in vitro. In this study, we found that CS also exacerbated Pseudomonas-induced ALI in mice. We demonstrated that lung microvascular endothelial cells (ECs) isolated from mice exposed to CS had a greater permeability or incomplete recovery after challenges by LPS and thrombin. Histone deacetylase (HDAC) 6 deacetylates proteins essential for maintenance of endothelial barrier function. We found that HDAC6 phosphorylation at serine-22 was increased in lung tissues of mice exposed to CS and in lung ECs exposed to cigarette smoke extract (CSE). Inhibition of HDAC6 attenuated CSE-induced increases in EC permeability and CS priming of ALI. Similar barrier protection was provided by the microtubule stabilizer taxol, which preserved α-tubulin acetylation. CSE decreased α-tubulin acetylation and caused microtubule depolymerization. In coordination with increased HDAC6 phosphorylation, CSE inhibited Akt and activated glycogen synthase kinase (GSK)-3β; these effects were ameliorated by the antioxidant N-acetyl cysteine. Our results suggest that CS increases lung EC permeability, thereby enhancing susceptibility to ALI, likely through oxidative stress-induced Akt inactivation and subsequent GSK-3β activation. Activated GSK-3β may activate HDAC6 via phosphorylation of serine-22, leading to α-tubulin deacetylation and microtubule disassembly. Inhibition of HDAC6 may be a novel therapeutic option for ALI in cigarette smokers. PMID:26452072

  2. Isoflurane ameliorates acute lung injury by preserving epithelial tight junction integrity

    PubMed Central

    Englert, Joshua A.; Macias, Alvaro A.; Amador-Munoz, Diana; Vera, Miguel Pinilla; Isabelle, Colleen; Guan, Jiazhen; Magaoay, Brady; Velandia, Margarita Suarez; Coronata, Anna; Lee, Awapuhi; Fredenburgh, Laura E.; Culley, Deborah J.; Crosby, Gregory; Baron, Rebecca M.

    2015-01-01

    Background Isoflurane may be protective in pre-clinical models of lung injury but its use in patients with lung injury remains controversial and the mechanism of its protective effects remains unclear. We hypothesized that this protection is mediated at the level of alveolar tight junctions and investigated the possibility in a two-hit model of lung injury that mirrors human acute respiratory distress syndrome. Methods Wild-type mice were treated with isoflurane one hour after exposure to nebulized endotoxin (n=8) or saline control (n=9) then allowed to recover for 24 hrs prior to mechanical ventilation (MV, tidal volume 15 mL/kg, 2 hrs) producing ventilator-induced lung injury. Mouse lung epithelial cells were similarly treated with isoflurane one hour after exposure to lipopolysaccharide. Cells were cyclically stretched the following day to mirror the MV protocol used in vivo. Results Mice treated with isoflurane following exposure to inhaled endotoxin and prior to MV exhibited significantly less physiologic lung dysfunction. These effects appeared to be mediated by decreased vascular leak, but not altered inflammatory indices. Mouse lung epithelial cells treated with lipopolysaccharide and cyclic stretch and lungs harvested from mice following treatment with lipopolysaccharide and MV had decreased levels of a key tight junction protein (i.e. zona occludens 1) that was rescued by isoflurane treatment. Conclusions Isoflurane rescued lung injury induced by a two-hit model of endotoxin exposure followed by MV by maintaining the integrity of the alveolar-capillary barrier possibly by modulating the expression of a key tight junction protein. PMID:26068207

  3. Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

    SciTech Connect

    Lee, Ye-Ji; Lee, Seung-Hae; Youn, Young-So; Choi, Ji-Yeon; Song, Keung-Sub; Cho, Min-Sun; Kang, Jihee Lee

    2012-08-15

    Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment. -- Highlights: ►Mer expression is restored by TAPI-0 treatment in bleomycin-stimulated lung. ►Mer signaling is enhanced by TAPI-0 treatment in bleomycin-stimulated lung. ►TAPI-0 enhances efferocytosis and promotes resolution of lung injury.

  4. Crosstalk between ACE2 and PLGF regulates vascular permeability during acute lung injury

    PubMed Central

    Wang, Lantao; Li, Yong; Qin, Hao; Xing, Dong; Su, Jie; Hu, Zhenjie

    2016-01-01

    Angiotensin converting enzyme 2 (ACE2) treatment suppresses the severity of acute lung injury (ALI), through antagonizing hydrolyzing angiotensin II (AngII) and the ALI-induced apoptosis of pulmonary endothelial cells. Nevertheless, the effects of ACE2 on vessel permeability and its relationship with placental growth factor (PLGF) remain ill-defined. In the current study, we examined the relationship between ACE2 and PLGF in ALI model in mice. We used a previously published bleomycin method to induce ALI in mice, and treated the mice with ACE2. We analyzed the levels of PLGF in these mice. The mouse lung vessel permeability was determined by a fluorescence pharmacokinetic assay following i.v. injection of 62.5 µg/kg Visudyne. PLGF pump or soluble Flt-1 (sFlt-1) pump was given to augment or suppress PLGF effects, respectively. The long-term effects on lung function were determined by measurement of lung resistance using methacholine. We found that ACE2 treatment did not alter PLGF levels in lung, but antagonized the effects of PLGF on increases of lung vessel permeability. Ectogenic PLGF abolished the antagonizing effects of ACE2 on the vessel permeability against PLGF. On the other hand, suppression of PLGF signaling mimicked the effects of ACE2 on the vessel permeability against PLGF. The suppression of vessel permeability resulted in improvement of lung function after ALI. Thus, ACE2 may antagonize the PLGF-mediated increases in lung vessel permeability during ALI, resulting in improvement of lung function after ALI. PMID:27158411

  5. Time-dependent changes of autophagy and apoptosis in lipopolysaccharide-induced rat acute lung injury

    PubMed Central

    Lin, Li; Zhang, Lijun; Yu, Liangzhu; Han, Lu; Ji, Wanli; Shen, Hui; Hu, Zhenwu

    2016-01-01

    Objective(s): Abnormal lung cell death including autophagy and apoptosis is the central feature in acute lung injury (ALI). To identify the cellular mechanisms and the chronology by which different types of lung cell death are activated during lipopolysaccharide (LPS)-induced ALI, we decided to evaluate autophagy (by LC3-II and autophagosome) and apoptosis (by caspase-3) at different time points after LPS treatment in a rat model of LPS-induced ALI. Materials and Methods: Sprague-Dawley rats were randomly divided into two groups: control group and LPS group. ALI was induced by LPS intraperitoneal injection (3 mg/kg). The lung tissues were collected to measure lung injury score by histopathological evaluation, the protein expression of LC3-II and caspase-3 by Western blot, and microstructural changes by electron microscopy analysis. Results: During ALI, lung cell death exhibited modifications in the death process at different stages of ALI. At early stages (1 hr and 2 hr) of ALI, the mode of lung cell death started with autophagy in LPS group and reached a peak at 2 hr. As ALI process progressed, apoptosis was gradually increased in the lung tissues and reached its maximal level at later stages (6 hr), while autophagy was time-dependently decreased. Conclusion: These findings suggest that activated autophagy and apoptosis might play distinct roles at different stages of LPS-induced ALI. This information may enhance the understanding of lung pathophysiology at the cellular level during ALI and pulmonary infection, and thus help optimize the timing of innovating therapeutic approaches in future experiments with this model. PMID:27482344

  6. Neutrophils and their Fcγ receptors are essential in a mouse model of transfusion-related acute lung injury

    PubMed Central

    Looney, Mark R.; Su, Xiao; Van Ziffle, Jessica A.; Lowell, Clifford A.; Matthay, Michael A.

    2006-01-01

    Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion-related mortality. To explore the pathogenesis of TRALI, we developed an in vivo mouse model based on the passive transfusion of an MHC class I (MHC I) mAb (H2Kd) to mice with the cognate antigen. Transfusion of the MHC I mAb to BALB/c mice produced acute lung injury with increased excess lung water, increased lung vascular and lung epithelial permeability to protein, and decreased alveolar fluid clearance. There was 50% mortality at a 2-hour time point after Ab administration. Pulmonary histology and immunohistochemistry revealed prominent neutrophil sequestration in the lung microvasculature that occurred concomitantly with acute peripheral blood neutropenia, all within 2 hours of administration of the mAb. Depletion of neutrophils by injection of anti-granulocyte mAb Gr-1 protected mice from lung injury following MHC I mAb challenge. FcRγ–/– mice were resistant to MHC I mAb–induced lung injury, while adoptive transfer of wild-type neutrophils into the FcRγ–/– animals restored lung injury following MHC I mAb challenge. In conclusion, in a clinically relevant in vivo mouse model of TRALI using an MHC I mAb, the mechanism of lung injury was dependent on neutrophils and their Fcγ receptors. PMID:16710475

  7. Therapeutic Effect of the Tuber of Alisma orientale on Lipopolysaccharide-Induced Acute Lung Injury

    PubMed Central

    Kwun, Min Jung; Choi, Jun-Yong; Ahn, Kyung-Seop; Oh, Sei-Ryang; Lee, Yong Gyu; Christman, John W.; Sadikot, Ruxana T.

    2013-01-01

    Although Alisma orientale, an ethnic herb, has been prescribed for treating various diseases in Asian traditional medicine, experimental evidence to support its therapeutic effects is lacking. Here, we sought to determine whether A. orientale has a therapeutic effect on acute lung injury (ALI). Ethanol extract of the tuber of A. orientale (EEAO) was prepared and fingerprinted by HPLC for its constituents. Mice received an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) for the induction of ALI. At 2 h after LPS treatment, mice received an intratracheal (i.t.) spraying of various amounts of EEAO to the lung. Bioluminescence imaging of transgenic NF-κB/luciferase reporter mice shows that i.t. EEAO posttreatment suppressed lung inflammation. In similar experiments with C57BL/6 mice, EEAO posttreatment significantly improved lung inflammation, as assessed by H&E staining of lung sections, counting of neutrophils in bronchoalveolar lavage fluid, and semiquantitative RT-PCR analyses of proinflammatory cytokines and Nrf2-dependent genes in the inflamed lungs. Furthermore, EEAO posttreatment enhanced the survival of mice that received a lethal dose of LPS. Together, our results provide evidence that A. orientale has a therapeutic effect on ALI induced by sepsis. PMID:23983806

  8. Natural Antioxidant Betanin Protects Rats from Paraquat-Induced Acute Lung Injury Interstitial Pneumonia

    PubMed Central

    Ma, Deshun; Zhang, Miao; Yang, Xuelian; Tan, Dehong

    2015-01-01

    The effect of betanin on a rat paraquat-induced acute lung injury (ALI) model was investigated. Paraquat was injected intraperitoneally at a single dose of 20 mg/kg body weight, and betanin (25 and 100 mg/kg/d) was orally administered 3 days before and 2 days after paraquat administration. Rats were sacrificed 24 hours after the last betanin dosage, and lung tissue and bronchoalveolar lavage fluid (BALF) were collected. In rats treated only with paraquat, extensive lung injury characteristic of ALI was observed, including histological changes, elevation of lung : body weight ratio, increased lung permeability, increased lung neutrophilia infiltration, increased malondialdehyde (MDA) and myeloperoxidase (MPO) activity, reduced superoxide dismutase (SOD) activity, reduced claudin-4 and zonula occluden-1 protein levels, increased BALF interleukin (IL-1) and tumor necrosis factor (TNF)-α levels, reduced BALF IL-10 levels, and increased lung nuclear factor kappa (NF-κB) activity. In rats treated with betanin, paraquat-induced ALI was attenuated in a dose-dependent manner. In conclusion, our results indicate that betanin attenuates paraquat-induced ALI possibly via antioxidant and anti-inflammatory mechanisms. Thus, the potential for using betanin as an auxilliary therapy for ALI should be explored further. PMID:25861636

  9. Effects of anesthetic regimes on inflammatory responses in a rat model of acute lung injury

    PubMed Central

    Fortis, Spyridon; Spieth, Peter M.; Lu, Wei-Yang; Parotto, Matteo; Haitsma, Jack J; Slutsky, Arthur S.; Zhong, Nanshan; Mazer, C. David; Zhang, Haibo

    2016-01-01

    Background Gamma amino butyric acid (GABA) is the major inhibitory neurotransmitter through activation of GABA receptors. Volatile anesthetics activate type A (GABAA) receptors resulting in inhibition of synaptic transmission. Lung epithelial cells have been recently found to express GABAA receptors that exert anti-inflammatory properties. We hypothesized that the volatile anesthetic sevoflurane (SEVO) attenuates lung inflammation through activation of lung epithelial GABAA receptors. Methods Sprague-Dawley rats were anesthetized with SEVO or ketamine/xylazine (KX). Acute lung inflammation was induced by intratracheal instillation of endotoxin, followed by mechanical ventilation for 4 h at a tidal volume of 15 mL/kg without positive end-expiratory pressure (two-hit lung injury model). To examine the specific effects of GABA, healthy human bronchial epithelial cells (BEAS-2B) were challenged with endotoxin in the presence and absence of GABA with and without addition of the GABAA receptor antagonist picrotoxin. Results Anesthesia with SEVO improved oxygenation and reduced pulmonary cytokine responses compared to KX. This phenomenon was associated with increased expression of the π subunit of GABAA receptors and glutamic acid decarboxylase (GAD). The endotoxin-induced cytokine release from BEAS-2B cells was attenuated by the treatment with GABA, which was reversed by the administration of picrotoxin. Conclusion Anesthesia with SEVO suppresses pulmonary inflammation thus protects the lung from the two-hit injury. The anti-inflammatory effect of SEVO is likely due to activation of pulmonary GABAA signaling pathways. PMID:22711173

  10. Molecular studies of the immunological effects of the sevoflurane preconditioning in the liver and lung in a rat model of liver ischemia/reperfusion injury.

    PubMed

    Mikrou, Angeliki; Kalimeris, Konstantinos A; Lilis, Ioannis; Papoutsidakis, Nikolaos; Nastos, Konstantinos; Papadaki, Helen; Kostopanagiotou, Georgia G; Zarkadis, Ioannis K

    2016-04-01

    Sevoflurane has been shown to improve ischemia/reperfusion injury (IRI) through several mechanisms, including amelioration of inflammatory response. However, there haven't been any studies considering the potential role of the complement system in sevoflurane-mediated amelioration of ischemia/reperfusion injury. Our purpose was to investigate the molecular mechanisms involved in sevoflurane preconditioning in liver and lung injury induced by liver ischemia-reperfusion (LIR), giving emphasis to the immunological mechanisms. In order to do that, fifty male Wistar rats were randomly allocated in five groups (n=10 each): Animals in group LIR received ketamine and xylazine and were then subjected to ischemia of the right and median hepatic lobe for 45 min and reperfusion for 6h. Group SEVO/LIR received sevoflurane and then LIR was induced, as in group LIR. Animals in group SHAM/LIR were anesthetized with ketamine and xylazine and then laparotomy followed. Group SHAM/SEVO received sevoflurane for 30 min and then laparotomy followed. Finally, in group VEN, animals only received ketamine and xylazine. Our results showed that sevoflurane preconditioning significantly improved liver-biochemical tests (decreased Alanine transaminase (ALT), Alkaline phosphatase (ALP), Aspartate transaminase (AST) and Alkaline phosphatase (ALP) levels) and limited inflammatory cell infiltration in BALF. Additionally, compared with the LIR group, the reduction in plasma C3 was significantly reduced in the SEVO/LIR group. No significant differences were observed in histological examination in the liver and lung. Immunostaining of the liver for Intracellular Adhesion Molecule 1 (ICAM1) however, showed a decrease in ICAM1 levels in the SEVO/LIR group. In the lung, sevoflurane seemed to exert no effect in ICAM1 levels. Caspase 3 (CASP3) levels in the liver and the lung also appeared unaffected by sevoflurane preconditioning. In the SEVO/LIR group, ICAM1 mRNA expression was significantly reduced in

  11. Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients.

    PubMed

    Shirali, Anushree C; Perazella, Mark A; Gettinger, Scott

    2016-08-01

    Immune checkpoint inhibitors that target the programmed death 1 (PD-1) signaling pathway have recently been approved for use in advanced pretreated non-small cell lung cancer and melanoma. Clinical trial data suggest that these drugs may have adverse effects on the kidney, but these effects have not been well described. We present 6 cases of acute kidney injury in patients with lung cancer who received anti-PD-1 antibodies, with each case displaying evidence of acute interstitial nephritis (AIN) on kidney biopsy. All patients were also treated with other drugs (proton pump inhibitors and nonsteroidal anti-inflammatory drugs) linked to AIN, but in most cases, use of these drugs long preceded PD-1 inhibitor therapy. The association of AIN with these drugs in our patients raises the possibility that PD-1 inhibitor therapy may release suppression of T-cell immunity that normally permits renal tolerance of drugs known to be associated with AIN. PMID:27113507

  12. Lung Postmortem Autopsy Revealing Extramedullary Involvement in Multiple Myeloma Causing Acute Respiratory Distress Syndrome

    PubMed Central

    Ravinet, Aurélie; Perbet, Sébastien; Guièze, Romain; Guérin, Renaud; Gayraud, Guillaume; Aliane, Jugurtha; Tremblay, Aymeric; Pascal, Julien; Ledoux, Albane; Chaleteix, Carine; Dechelotte, Pierre; Bay, Jacques-Olivier; Bazin, Jean-Etienne; Constantin, Jean-Michel

    2014-01-01

    Pulmonary involvement with multiple myeloma is rare. We report the case of a 61-year-old man with past medical history of chronic respiratory failure with emphysema, and a known multiple myeloma (Durie and Salmon stage III B and t(4;14) translocation). Six months after diagnosis and first line of treatment, he presented acute dyspnea with interstitial lung disease. Computed tomography showed severe bullous emphysema and diffuse, patchy, multifocal infiltrations bilaterally with nodular character, small bilateral pleural effusions, mediastinal lymphadenopathy, and a known lytic lesion of the 12th vertebra. He was treated with piperacillin-tazobactam, amikacin, oseltamivir, and methylprednisolone. Finally, outcome was unfavourable. Postmortem analysis revealed diffuse and nodular infracentimetric infiltration of the lung parenchyma by neoplastic plasma cells. Physicians should be aware that acute respiratory distress syndrome not responding to treatment of common causes could be a manifestation of the disease, even with negative BAL or biopsy and could be promptly treated with salvage therapy. PMID:25165587

  13. Acute lung injury after platelet transfusion in a patient with dengue fever

    PubMed Central

    Karoli, Ritu; Bhat, Sanjay; Fatima, Jalees; Verma, Pankaj

    2014-01-01

    Transfusion-related acute lung injury (TRALI) is a serious clinical syndrome associated with the transfusion of plasmacontaining blood components. Recently, TRALI has come to be recognized as the leading cause of transfusion-related mortality. This complication typically presents as shortness of breath, hypoxemia, hypotension, fever, and non cardiogenic pulmonary edema, occurring within 6 h after transfusion. Although the mechanism of TRALI has not been exactly known, it has been associated with human leukocyte antigen antibodies and with biologically active mediators in stored cellular blood components. We, hereby, present a case of a patient with dengue fever who developed acute lung injury (ALI), presumably TRALI, after transfusion of platelet concentrates. He was treated with supportive measures and mechanical ventilation. Greater knowledge and increased awareness especially amongst the clinicians regarding TRALI is needed for prevention and treatment of this potentially severe complication of blood/component transfusion. PMID:25161356

  14. [Lung diseases complicating acute poisoning with psychotropic drugs].

    PubMed

    Offenstadt, G; Gabillet, J M; Hericord, P; Pinta, P; Tembely, A; Amstutz, P

    1983-03-01

    474 patients admitted in ICU between 1976 and 1981 were retrospectively analysed. Pneumonia (P) was assessed by condensation on chest X ray. P developed in 14,3%. 24 hours after admission 77,6% of P had appeared. Initial location was unilateral in 79,4% with predilection to the inferior half of the right lung. Fever was almost constant (89,5%). Promoting factors were observed: delay between ingestion and admission, vomiting and tracheobronchial embarrassment, coma depth. Recovery was simple in 83,3%. Among the 14 deads, 6 died because only of p, in 4 other P was aggravating. Duration in ICU was much longer when P was present (9 +/- 8,1 days) than when P was absent (2,5 +/- 2,1) p less than 0,001. PMID:6612727

  15. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    SciTech Connect

    Wang, Chaoyun; Huang, Qingxian; Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai; Bai, Xianyong

    2013-11-01

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO{sub 2}), carbon dioxide tension, pH, and the PaO{sub 2}/fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22{sup phox} levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation may

  16. CAF1-knockout mice are more susceptive to lipopolysaccharide-induced acute lung injury

    PubMed Central

    Shi, Jia-Xin; Li, Jia-Shu; Hu, Rong; Li, Xiao-Min; Wang, Hong

    2016-01-01

    The carbon catabolite repressor protein 4 (CCR4)–negative on TATA (NOT) complex includes multiple subunits and is conserved in the eukaryotic cells. The CCR4–NOT complex can regulate gene expression at different levels. Two subunits of the CCR4–NOT complex, CCR4 and CCR4-associated factor 1 (CAF1), possess deadenylase activity. In yeast, the deadenylase activity is mainly provided by the CCR4 subunit; however, the deadenylase activity is provided by both CCR4 and CAF1 in other eukaryotes. A previous study reported that CAF1 but not CCR4 is required for the decay of a reporter mRNA with AU-rich elements. Our previous study showed that CAF1 is involved in the regulation of intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) expression. Both ICAM-1 and IL-8 play crucial roles in acute lung injury. In the present study, we examined the effects of CAF1 deficiency on IL-8 and ICAM-1 expression and acute lung injury in mice. Here we showed that there were no differences between the wild-type and CAF1-knockout mice on phenotypes. The lung histology and protein and mRNA levels of IL-8 and ICAM-1 in unstimulated wild-type mice were comparable to those in unstimulated CAF1-knockout mice. However, lipopolysaccharide stimulation led to more severe lung histological injury and greatly higher IL-8 and ICAM-1 expression in CAF1-knockout mice compared to the wild-type mice. These results, together with our previous study, suggest that CAF1 is involved in the regulation of lipopolysaccharide-stimulated IL-8 and ICAM-1 expression in vivo and affects the progression of acute lung injury. PMID:27358572

  17. [Protective effect of rupatadine against oleic acid-induced acute lung injury in rabbits].

    PubMed

    Zhang, Lin-Li; Lu, Jing; Yu, Shu-Qin; He, Jian-Lin; Zhou, Min; Xu, Guang-Lin

    2007-03-01

    Acute lung injury (ALI) makes up a spectrum of disease that is commonly defined as "acute non-cardiogenic edematous lung injury". It may contribute to morbidity and mortality in the critically ill patient in the intensive care unit. ALI was induced by oleic acid in rabbits. During the experiment, blood samples were taken from cervical artery and subjected to blood-gas analysis at different time points after oleic acid injection. Shortly after the rabbits were killed at 3 hour after iv OA injection, bronchoalveolar lavage fluid (BALF) was colleted, and the concentrations of protein, platelet-activating factor (PAF), intercellular adhesion molecule-1 (ICAM-1), interleukin 8 (IL-8) in BALF were then measured by ELISA. The ratio of wet to dry weight (W/D) of left lung was calculated to assess alveolar edema. Lung tissue was fixed in formaldehyde and stained with HE, and examined under a light microscope. The OA-induced elevation of arterial blood oxygen pressure was inhibited, as well as PAF, ICAM-1, IL-8 in BALF in rupatadine group. Furthermore, rupatadine also decreased the concentration of protein in BALF and inhibited the increase of the W/D weight ratio significantly. Light microscopic findings showed that the damage in rupatadine groups was far less severe than that in OA model group. Pretreatment with rupatadine has a beneficial effect on acute lung injury induced by oleic acid in rabbits. The ultimate reduction of inflammatory factors was involved, at least in part, in the mechanism of action of rupatadine effects. PMID:17520822

  18. Kidney-lung connections in acute and chronic diseases: current perspectives.

    PubMed

    Visconti, Luca; Santoro, Domenico; Cernaro, Valeria; Buemi, Michele; Lacquaniti, Antonio

    2016-06-01

    Lung and kidney functions are intimately related in both health and disease. The regulation of acid-base equilibrium, modification of partial pressure of carbon dioxide and bicarbonate concentration, and the control of blood pressure and fluid homeostasis all closely depend on renal and pulmonary activities. These interactions begin in fetal age and are often responsible for the genesis and progression of diseases. In gestational age, urine is a fundamental component of the amniotic fluid, acting on pulmonary maturation and growth. Moreover, in the first trimester of pregnancy, kidney is the main source of proline, contributing to collagen synthesis and lung parenchyma maturation. Pathologically speaking, the kidneys could become damaged by mediators of inflammation or immuno-mediated factors related to a primary lung pathology or, on the contrary, it could be the renal disease that determines a consecutive pulmonary damage. Furthermore, non immunological mechanisms are frequently involved in renal and pulmonary diseases, as observed in chronic pathologies such as sleep apnea syndrome, pulmonary hypertension, progressive renal disease and hemodialysis. Kidney damage has also been related to mechanical ventilation. The aim of this review is to describe pulmonary-renal interactions and their related pathologies, underscoring the need for a close collaboration between intensivists, pneumologists and nephrologists. PMID:26940339

  19. Noninvasive In Vivo Quantification of Neutrophil Elastase Activity in Acute Experimental Mouse Lung Injury

    PubMed Central

    Kossodo, Sylvie; Zhang, Jun; Groves, Kevin; Cuneo, Garry J.; Handy, Emma; Morin, Jeff; Delaney, Jeannine; Yared, Wael; Rajopadhye, Milind; Peterson, Jeffrey D.

    2011-01-01

    We developed a neutrophil elastase-specific near-infrared fluorescence imaging agent, which, combined with fluorescence molecular tomographic imaging, allowed us to detect and quantify neutrophil elastase activity in vivo, in real time, and noninvasively in an acute model of lung injury (ALI). Significantly higher fluorescent signal was quantified in mice with LPS/fMLP-induced ALI as compared to healthy controls, correlating with increases in the number of bronchoalveolar lavage cells, neutrophils, and elastase activity. The agent was significantly activated ex vivo in lung sections from ALI but not from control mice, and this activation was ablated by the specific inhibitor sivelestat. Treatment with the specific inhibitor sivelestat significantly reduced lung signal in mice with ALI. These results underscore the unique ability of fluorescence molecular imaging to quantify specific molecular processes in vivo, crucial for understanding the mechanisms underlying disease progression and for assessing and monitoring novel pharmacological interventions. PMID:21941648

  20. A case of acute fibrinous and organizing pneumonia during early postoperative period after lung transplantation.

    PubMed

    Alici, I O; Yekeler, E; Yazicioglu, A; Turan, S; Tezer-Tekce, Y; Demirag, F; Karaoglanoglu, N

    2015-04-01

    Acute fibrinous and organizing pneumonia (AFOP) is a distinct histologic pattern usually classified under the term chronic lung allograft dysfunction. We present a 48-year-old female patient who experienced AFOP during the 2nd week of double lung transplantation for pulmonary Langerhans cell histiocytosis and secondary pulmonary hypertension. During the 8th day after transplantation, fever and neutrophilia developed together with bilateral consolidation. Infection markers were elevated. Despite coverage of a full antimicrobial spectrum, the situation progressed. The patient was diagnosed with AFOP with transbronchial biopsy. The infiltration resolved and the patient improved dramatically with the initiation of pulse corticosteroid treatment. AFOP should be suspected when there is a pulmonary consolidation after lung transplantation, even in the very early post-transplantation period. Several causes, such as alveolar damage and drug reactions, should be considered in the differential diagnosis. PMID:25891742

  1. Transfusion-related acute lung injury: transfusion, platelets and biological response modifiers.

    PubMed

    Tariket, Sofiane; Sut, Caroline; Hamzeh-Cognasse, Hind; Laradi, Sandrine; Pozzetto, Bruno; Garraud, Olivier; Cognasse, Fabrice

    2016-05-01

    Transfusion-related acute lung injury (TRALI) may be induced by plasma, platelet concentrates and red blood cell concentrates. The mechanism leading to TRALI is thought to involve two steps. The priming step consists of previous inflammatory pathological conditions or external factors attracting leukocytes to lung vessels and creating conditions favorable for the second step, in which anti-HLA or anti-HNA antibodies or biologically active lipids, usually in transfused blood products, stress leukocytes and inflame lung epithelia. Platelets may be involved in the pathogenesis of TRALI because of their secretory potential and capacity to interact with other immune cells. There is no drug based-prophylaxis, but transfusion strategies are used to mitigate the risk of TRALI. PMID:26855042

  2. [Protective effect of curcumin on oleic-induced acute lung injury in rats].

    PubMed

    Zhu, Rui-fang; Zhou, Min; He, Jian-lin; Ding, Fu-yun; Yu, Shu-qin; Xu, Guang-lin

    2008-09-01

    To investigate the effect of curcumine on acute lung injury induced by oleic acid in rat and the possible mechanism of action. The rats were divided into 6 groups randomly: normal group, control group, curcumine groups (5, 10, 20 mg x kg(-1)) and dexamethasone group (1 mg x kg(-1)). During the experiment, acute lung injury was induced by oleic acid in rat. The changes of dynamic lung compliance were recorded by anrise 2005 pulmonary function test apparatus, light microscope was used to examine histological changes and lung index as well as wet to dry weight ratio was calculated by weighting method. Lung vascular permeability and protein level in BALF were detected by ultraviolet spectrophotometry, and the concentrations of TNF-alpha, IL-6 and IL-10 in BALF were measured by enzyme linked immunosorbent assay (ELISA). The result showed that the changes of pulmonary compliance were inhibited and pulmonary function was improved by curcumine. The OA-induced elevation of lung index was restrained, as well as wet to dry weight ratio, lung vascular permeability, protein level, TNF-alpha (250.4 +/- 21.6 vs. 172.53 +/- 14.88, 122.2 +/- 10.98, 108.69 +/- 3.39) ng x L(-1), IL-6 (763.6 +/- 88.33 vs. 207.41 +/- 15.55, 172.13 +/- 21.91, 142.92 +/- 4.32) ng x L(-1) in BALF in curcumine groups, IL-10 (98.90 +/- 2.99 vs. 208.44 +/- 16.30, 218.43 +/- 6.23, 252.70 +/- 20.58) ng x L(-1) in BALF was increased, respectively significantly. Light microscope findings shown that the impairment in curcumine groups was far less severe than that in model groups. Pretreatment of curcumine showed beneficial effect on acute lung injury induced by oleic acid in rats. The mediation of both proinflammatory factor and anti-inflammatory factor by curcumine may be involved in mechanism of action of curcumine effects. PMID:19066061

  3. Sexual dimorphism in lung function responses to acute influenza A infection

    PubMed Central

    Larcombe, Alexander N.; Foong, Rachel E.; Bozanich, Elizabeth M.; Berry, Luke J.; Garratt, Luke W.; Gualano, Rosa C.; Jones, Jessica E.; Dousha, Lovisa F.; Zosky, Graeme R.; Sly, Peter D.

    2011-01-01

    Please cite this paper as: Larcombe et al. (2011) Sexual dimorphism in lung function responses to acute influenza A infection. Influenza and Other Respiratory Viruses 5(5), 334–342. Background  Males are generally more susceptible to respiratory infections; however, there are few data on the physiological responses to such infections in males and females. Objectives  To determine whether sexual dimorphism exists in the physiological/inflammatory responses of weanling and adult BALB/c mice to influenza. Methods  Weanling and adult mice of both sexes were inoculated with influenza A or appropriate control solution. Respiratory mechanics, responsiveness to methacholine (MCh), viral titre and bronchoalveolar lavage (BAL) cellular inflammation/cytokines were measured 4 (acute) and 21 (resolution) days post‐inoculation. Results  Acute infection impaired lung function and induced hyperresponsiveness and cellular inflammation in both sexes at both ages. Males and females responded differently with female mice developing greater abnormalities in tissue damping and elastance and greater MCh responsiveness at both ages. BAL inflammation, cytokines and lung viral titres were similar between the sexes. At resolution, all parameters had returned to baseline levels in adults and weanling males; however, female weanlings had persisting hyperresponsiveness. Conclusions  We identified significant differences in the physiological responses of male and female mice to infection with influenza A, which occurred in the absence of variation in viral titre and cellular inflammation. PMID:21668688

  4. Effect of methylsulfonylmethane on paraquat-induced acute lung and liver injury in mice.

    PubMed

    Amirshahrokhi, Keyvan; Bohlooli, Shahab

    2013-10-01

    Methylsulfonylmethane (MSM) is a natural organosulfur compound that exhibits antioxidative and anti-inflammatory effects. This study was carried out to investigate the effect of MSM on paraquat (PQ)-induced acute lung and liver injury in mice. A single dose of PQ (50 mg/kg, i.p.) induced acute lung and liver toxicity. Mice were treated with MSM (500 mg/kg/day, i.p.) for 5 days. At the end of the experiment, animals were euthanized, and lung and liver tissues were collected for histological and biochemical analysis. Tissue samples were used to determine malondialdehyde (MDA), myeloperoxidase (MPO), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and tumor necrosis factor-α (TNF-α) levels. Blood samples were used to measure plasma alanine transaminase (ALT), γ-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Histological examination indicated that MSM decreased lung and liver damage caused by PQ. Biochemical results showed that MSM treatment significantly reduced tissue levels of MDA, MPO, and TNF-α, while increased the levels of SOD, CAT, and GSH compared with PQ group. MSM treatment also significantly reduced plasma levels of ALT, GGT, and ALP. These findings suggest that MSM as a natural product attenuates PQ-induced pulmonary and hepatic oxidative injury. PMID:23595869

  5. Lobeline improves acute lung injury via nuclear factor-κB-signaling pathway and oxidative stress.

    PubMed

    Li, Kun-Cheng; Ho, Yu-Ling; Chen, Cing-Yu; Hsieh, Wen-Tsong; Chang, Yuan-Shiun; Huang, Guan-Jhong

    2016-05-01

    Acute lung injury (ALI) is a severe, life-threatening medical condition whose pathogenesis is linked to neutrophil infiltration of the lung. Activation and recruitment of neutrophils to the lung is mostly attributed to the production of chemokines NO, IL-6, for instance. This study aims to investigate lobeline ability in reducing NO production, and nitric oxide synthase (iNOs) expression. Lobeline was tested by inhibiting phosphorylation of mitogen-activated protein kinases (MAPKs), NF-κB and IκBα in LPS-stimulated RAW 264.7 cells. When RAW 264.7 macrophages were given lobeline with LPS, a significant concentration-dependent inhibition of NO production was detected. In vivo tests, mice were either treated with normal saline, 10mg/kg dexmethasone or 5, 10, 20mg/kg lobeline intraperitoneally, and after an hour, the administration of 5mg/kg of LPS was given intratracheally. External performance, cytokines, MAPK pathways and antioxidative enzymes (AOEs) were also carried out to evaluate the effects of these drugs. This is the first investigation in which lobeline was found to effectively inhibit acute lung edema, which may provide a potential target for treating ALI. Lobeline may utilize MAPKs pathways as well as AOEs activity to attenuate LPS-induced nonspecific pulmonary inflammation. PMID:26702732

  6. Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis

    PubMed Central

    Lin, Wei-Chieh; Chen, Chang-Wen; Huang, Yu-Wen; Chao, Lee; Chao, Julie; Lin, Yee-Shin; Lin, Chiou-Feng

    2015-01-01

    Kallistatin, an endogenous plasma protein, exhibits pleiotropic properties in inhibiting inflammation, oxidative stress and apoptosis, as evidenced in various animal models and cultured cells. Here, we demonstrate that kallistatin levels were positively correlated with the concentration of total protein in bronchoalveolar lavage fluids (BALF) from patients with sepsis-related acute respiratory distress syndrome (ARDS), indicating a compensatory mechanism. Lower ratio of kallistatin to total protein in BALF showed a significant trend toward elevated neutrophil counts (P = 0.002) in BALF and increased mortality (P = 0.046). In lipopolysaccharide (LPS)-treated mice, expression of human kallistatin in lung by gene transfer with human kallistatin-encoding plasmid ameliorated acute lung injury (ALI) and reduced cytokine/chemokine levels in BALF. These mice exhibited attenuated lung epithelial apoptosis and decreased Fas/FasL expression compared to the control mice. Mouse survival was improved by kallistatin gene transfer or recombinant human kallistatin treatment after LPS challenge. In LPS-stimulated A549 human lung epithelial cells, kallistatin attenuated apoptosis, down-regulated Fas/FasL signaling, suppressed intracellular reactive oxygen species (ROS) and inhibited ROS-mediated NF-κB activation and inflammation. Furthermore, LPS-induced apoptosis was blocked by antioxidant N-acetylcysteine or NF-κB inhibitor via down-regulating Fas expression. These findings suggest the therapeutic potential of kallistatin for sepsis-related ALI/ARDS. PMID:26198099

  7. Role of activated neutrophils in chest trauma-induced septic acute lung injury.

    PubMed

    Perl, Mario; Hohmann, Christoph; Denk, Stephanie; Kellermann, Philipp; Lu, Dapeng; Braumüller, Sonja; Bachem, Max G; Thomas, Jörg; Knöferl, Markus W; Ayala, Alfred; Gebhard, Florian; Huber-Lang, Markus S

    2012-07-01

    More than 50% of severely injured patients have chest trauma. Second insults frequently result in acute lung injury (ALI), with sepsis being the main underlying condition. We aimed to develop a standardized, reproducible, and clinically relevant double-hit mouse model of ALI induced by chest trauma and polymicrobial sepsis and to investigate the pathophysiologic role of activated neutrophils. Lung contusion was applied to C57Bl/6 mice via a focused blast wave. Twenty-four hours later, sepsis was induced by cecal ligation and puncture. For polymorphonuclear leukocyte (PMN) depletion, animals received intravenous injections of PMN-depleting antibody. In response to blunt chest trauma followed by sepsis as well as after sepsis alone, a significant local and systemic inflammatory response with increased cytokine/chemokine levels in lung and plasma was observed. In contrast, lung apoptosis was markedly elevated only after a double hit. Intra-alveolar neutrophils and total bronchoalveolar lavage protein concentrations were markedly increased following isolated chest trauma or the combined insult, but not after sepsis alone. Lung myeloperoxidase activity was enhanced only in response to the double hit accompanied by histological disruption of the alveolar architecture, lung congestion, and marked cellular infiltrates. Neutrophil depletion significantly diminished lung interleukin 1β and interleukin 6 concentrations and reduced the degree of septic ALI. Here we have established a novel and highly reproducible mouse model of chest trauma-induced septic ALI characterizing a clinical relevant double-hit scenario. In particular, the depletion of neutrophils substantially mitigated the extent of lung injury, indicating a pathomechanistic role for neutrophils in chest trauma-induced septic ALI. PMID:22552016

  8. Upregulated Tim-3/galectin-9 expressions in acute lung injury in a murine malarial model.

    PubMed

    Liu, Jinfeng; Xiao, Siyu; Huang, Shiguang; Pei, Fuquan; Lu, Fangli

    2016-02-01

    Malaria is the most relevant parasitic disease worldwide, and severe malaria is characterized by cerebral edema, acute lung injury (ALI), and multiple organ dysfunctions; however, the mechanisms of lung damage need to be better clarified. In this study, we used Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) to elucidate the profiles of T cell immunoglobulin and mucin domain-3 (Tim-3) and its ligand galecin-9 (Gal-9) in the development of ALI. Mice were injected intraperitoneally with 10(6) PbANKA-infected red blood cells. The lungs and mediastinal lymph nodes (MLNs) were harvested at days 5, 10, 15, and 20 post infections (p.i.). The grade of lung injury was histopathologically evaluated. Tim-3- and Gal-9-positive cells in the lungs and MLNs were stained by immunohistochemistry, and the messenger RNA (mRNA) expressions of Tim-3, Gal-9, and related cytokines were assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Bronchoalveolar lavage fluid (BALF) analyses were performed from days 18 to 20 p.i. The results showed that the pathological severities in the lungs were increased with times and the total protein level in the BALFs was significantly elevated in PbANKA-infected mice. The numbers of Gal-9(+) and Tim-3(+) cells in the lungs were significantly increased, and the mRNA levels of both Gal-9 and Tim-3 in the lungs and MLNs were over-expressed in PbANKA-infected mice. In conclusion, our data suggested that Tim-3/Gal-9 may play a role in PbANKA-induced ALI. PMID:26494364

  9. T cell immunohistochemistry refines lung transplant acute rejection diagnosis and grading

    PubMed Central

    2013-01-01

    Objective Lung transplant volume has been increasing. However, inaccurate and uncertain diagnosis for lung transplant rejection hurdles long-term outcome due to, in part, interobserver variability in rejection grading. Therefore, a more reliable method to facilitate diagnosing and grading rejection is warranted. Method Rat lung grafts were harvested on day 3, 7, 14 and 28 post transplant for histological and immunohistochemical assessment. No immunosuppressive treatment was administered. We explored the value of interstitial T lymphocytes quantification by immunohistochemistry and compared the role of T cell immunohistochemistry with H&E staining in diagnosing and grading lung transplant rejection. Results Typical acute rejection from grade A1 to A4 was found. Rejection severity was heterogeneously distributed in one-third transplanted lungs (14/40): lesions in apex and center were more augmented than in the base and periphery of the grafts, respectively. Immunohistochemistry showed profound difference in T lymphocyte infiltration among grade A1 to A4 rejections. The coincidence rate of H&E and immunohistochemistry was 77.5%. The amount of interstitial T lymphocyte infiltration increased gradually with the upgrading of rejection. The statistical analysis demonstrated that the difference in the amount of interstitial T lymphocytes between grade A2 and A3 was not obvious. However, T lymphocytes in lung tissue of grade A4 were significantly more abundant than in other grades. Conclusions Rejection severity was heterogeneously distributed within lung grafts. Immunohistochemistry improves the sensitivity and specificity of rejection diagnosis, and interstitial T lymphocyte quantitation has potential value in diagnosing and monitoring lung allograft rejection. Virtual slides The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1536075282108217. PMID:24330571

  10. The impact of sodium aescinate on acute lung injury induced by oleic acid in rats.

    PubMed

    Wei, Tian; Tong, Wang; Wen-ping, Sun; Xiao-hui, Deng; Qiang, Xue; Tian-shui, Li; Zhi-fang, Chen; Hong-fang, Jin; Li, Ni; Bin, Zhao; Jun-bao, Du; Bao-ming, Ge

    2011-12-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high rates of morbidity and mortality. Currently, several surfactant or anti-inflammatory drugs are under test as treatments for ALI. Sodium aescinate (SA) has been shown to exert anti-inflammatory and antiedematous effects. In the present work, the authors explored the effects of SA and the possible mechanisms of SA action in rats with ALI induced by oleic acid (OA) administration. Eight groups of rats received infusions of normal saline (NS) or OA. Rats exposed to OA were pretreated with 1 mg/kg of SA, or posttreated with SA at low (1 mg/kg), medium (2 mg/kg), or high (6 mg/kg) dose; a positive-control group received methylprednisolone. The pressure of oxygen in arterial blood (P(O(2))) levels, the pulmonary wet/dry weight (W/D) ratios, and indices of quantitative assessment (IQA) of histological lung injury were obtained 2 or 6 hours after OA injection (0.1 mL/kg, intravenously). The levels of superoxide dismutase (SOD), malondialdehyde (MDA), matrix metalloproteinase gelatinase B (MMP-9), and tissue inhibitor of metalloproteinase (TIMP-1) in both plasma and lung tissue were also determined. Both pre- and posttreatment with SA improved OA-induced pulmonary injury, increased P(O(2)) and SOD values, lowered IQA scores, and decreased the lung W/D ratio and MDA and MMP-9 levels in plasma and lung tissue. SA appeared to abrogate OA-induced ALI by modulating the levels of SOD, MDA, and MMP-9 in plasma and lung tissue. PMID:22087513

  11. Genome-wide association mapping of acute lung injury in neonatal inbred mice

    PubMed Central

    Nichols, Jennifer L.; Gladwell, Wesley; Verhein, Kirsten C.; Cho, Hye-Youn; Wess, Jürgen; Suzuki, Oscar; Wiltshire, Tim; Kleeberger, Steven R.

    2014-01-01

    Reactive oxygen species (ROS) contribute to the pathogenesis of many acute and chronic pulmonary disorders, including bronchopulmonary dysplasia (BPD), a respiratory condition that affects preterm infants. However, the mechanisms of susceptibility to oxidant stress in neonatal lungs are not completely understood. We evaluated the role of genetic background in response to oxidant stress in the neonatal lung by exposing mice from 36 inbred strains to hyperoxia (95% O2) for 72 h after birth. Hyperoxia-induced lung injury was evaluated by using bronchoalveolar lavage fluid (BALF) analysis and pathology. Statistically significant interstrain variation was found for BALF inflammatory cells and protein (heritability estimates range: 33.6–55.7%). Genome-wide association mapping using injury phenotypes identified quantitative trait loci (QTLs) on chromosomes 1, 2, 4, 6, and 7. Comparative mapping of the chromosome 6 QTLs identified Chrm2 (cholinergic receptor, muscarinic 2, cardiac) as a candidate susceptibility gene, and mouse strains with a nonsynonymous coding single-nucleotide polymorphism (SNP) in Chrm2 that causes an amino acid substitution (P265L) had significantly reduced hyperoxia-induced inflammation compared to strains without the SNP. Further, hyperoxia-induced lung injury was significantly reduced in neonatal mice with targeted deletion of Chrm2, relative to wild-type controls. This study has important implications for understanding the mechanisms of oxidative lung injury in neonates.—Nichols, J. L., Gladwell, W., Verhein, K. C., Cho, H.-Y., Wess, J., Suzuki, O., Wiltshire, T., Kleeberger, S. R. Genome-wide association mapping of acute lung injury in neonatal inbred mice. PMID:24571919

  12. An acute adrenal insufficiency revealing pituitary metastases of lung cancer in an elderly patient

    PubMed Central

    Marmouch, Hela; Arfa, Sondes; Mohamed, Saoussen Cheikh; Slim, Tensim; Khochtali, Ines

    2016-01-01

    Metastases of solid tumors to the pituitary gland are often asymptomatic or appereas as with diabetes insipid us. Pituitary metastases more commonly affect the posterior lobe and the infundibulum than the anterior lobe. The presentation with an acute adrenal insufficiency is a rare event. A 69-year-old men presented with vomiting, low blood pressure and hypoglycemia. Hormonal exploration confirmed a hypopituitarism. Appropriate therapy was initiated urgently. The hypothalamic-pituitary MRI showed a pituitary hypertrophy, a nodular thickening of the pituitary stalk. The chest X Rays revealed pulmonary opacity. Computed tomography scan of the chest showed a multiples tumors with mediastinal lymphadenopathy. Bronchoscopy and biopsy demonstrated a pulmonary adenocarcinoma. Hence we concluded to a lung cancer with multiple pituitary and adrenal gland metastases. This case emphasizes the need for an etiological investigation of acute adrenal insufficiency after treatment of acute phase. PMID:27200139

  13. An acute adrenal insufficiency revealing pituitary metastases of lung cancer in an elderly patient.

    PubMed

    Marmouch, Hela; Arfa, Sondes; Mohamed, Saoussen Cheikh; Slim, Tensim; Khochtali, Ines

    2016-01-01

    Metastases of solid tumors to the pituitary gland are often asymptomatic or appereas as with diabetes insipid us. Pituitary metastases more commonly affect the posterior lobe and the infundibulum than the anterior lobe. The presentation with an acute adrenal insufficiency is a rare event. A 69-year-old men presented with vomiting, low blood pressure and hypoglycemia. Hormonal exploration confirmed a hypopituitarism. Appropriate therapy was initiated urgently. The hypothalamic-pituitary MRI showed a pituitary hypertrophy, a nodular thickening of the pituitary stalk. The chest X Rays revealed pulmonary opacity. Computed tomography scan of the chest showed a multiples tumors with mediastinal lymphadenopathy. Bronchoscopy and biopsy demonstrated a pulmonary adenocarcinoma. Hence we concluded to a lung cancer with multiple pituitary and adrenal gland metastases. This case emphasizes the need for an etiological investigation of acute adrenal insufficiency after treatment of acute phase. PMID:27200139

  14. Inhibition of SOCs Attenuates Acute Lung Injury Induced by Severe Acute Pancreatitis in Rats and PMVECs Injury Induced by Lipopolysaccharide.

    PubMed

    Wang, Guanyu; Zhang, Jingwen; Xu, Caiming; Han, Xiao; Gao, Yanyan; Chen, Hailong

    2016-06-01

    Acute lung injury (ALI) is a critical complication of the severe acute pancreatitis (SAP), characterized by increased pulmonary permeability with high mortality. Pulmonary microvascular endothelial cells (PMVECs) injury and apoptosis play a key role in ALI. Previous studies indicated that store-operated calcium entry (SOCE) could regulate a variety of cellular processes. The present study was to investigate the effects of SOCE inhibition on ALI induced by SAP in Sprague-Dawley rats, and PMVECs injury induced by lipopolysaccharide (LPS). Rat model of SAP-associated ALI were established by the retrograde infusion of sodium deoxycholate. Serum levels of amylase, TNF-α, and IL-6, histological changes, water content of the lung, oxygenation index, and ultrastructural changes of PMVECs were examined in ALI rats with or without store-operated Ca(2+) channels (SOCs) pharmacological inhibitor (2-aminoethoxydiphenyl borate, 2-APB) pretreatment. For in vitro studies, PMVECs were transiently transfected with or without small interfering RNA (siRNA) against calcium release-activated calcium channel protein1 (Orai1) and stromal interaction molecule1 (STIM1), the two main molecular constituents of SOCs, then exposed to LPS. The viability of PMVECs was determined. The expression of STIM1, Orai1, Bax, and caspase3, both in lung tissue and in PMVECs, were assessed by quantitative real-time PCR and western blot. Administration of sodium deoxycholate upregulated the expression of SOCs proteins in lung tissue. Similarly, the SOCs proteins were increased in PMVECs induced by LPS. 2-APB reduced the serum levels of amylase, TNF-α, and IL-6, and attenuated lung water content and histological findings. In addition, the decreased oxygenation index and ultrastructural damage in PMVECs associated with SAP were ameliorated after administration of 2-APB. Knockdown of STIM1 and Orai1 inhibited LPS-induced PMVECs death. Furthermore, blockade of SOCE significantly suppressed Orai1, STIM1, Bax

  15. Interleukin-22 ameliorates acute severe pancreatitis-associated lung injury in mice

    PubMed Central

    Qiao, Ying-Ying; Liu, Xiao-Qin; Xu, Chang-Qin; Zhang, Zheng; Xu, Hong-Wei

    2016-01-01

    AIM: To investigate the potential protective effect of exogenous recombinant interleukin-22 (rIL-22) on L-arginine-induced acute severe pancreatitis (SAP)-associated lung injury and the possible signaling pathway involved. METHODS: Balb/c mice were injected intraperitoneally with L-arginine to induce SAP. Recombinant mouse IL-22 was then administered subcutaneously to mice. Serum amylase levels and myeloperoxidase (MPO) activity in the lung tissue were measured after the L-arginine administration. Histopathology of the pancreas and lung was evaluated by hematoxylin and eosin (HE) staining. Expression of B cell lymphoma/leukemia-2 (Bcl-2), Bcl-xL and IL-22RA1 mRNAs in the lung tissue was detected by real-time PCR. Expression and phosphorylation of STAT3 were analyzed by Western blot. RESULTS: Serum amylase levels and MPO activity in the lung tissue in the SAP group were significantly higher than those in the normal control group (P < 0.05). In addition, the animals in the SAP group showed significant pancreatic and lung injuries. The expression of Bcl-2 and Bcl-xL mRNAs in the SAP group was decreased markedly, while the IL-22RA1 mRNA expression was increased significantly relative to the normal control group (P < 0.05). Pretreatment with PBS did not significantly affect the serum amylase levels, MPO activity or expression of Bcl-2, Bcl-xL or IL-22RA1 mRNA (P > 0.05). Moreover, no significant differences in the degrees of pancreatic and lung injuries were observed between the PBS and SAP groups. However, the serum amylase levels and lung tissue MPO activity in the rIL-22 group were significantly lower than those in the SAP group (P < 0.05), and the injuries in the pancreas and lung were also improved. Compared with the PBS group, rIL-22 stimulated the expression of Bcl-2, Bcl-xL and IL-22RA1 mRNAs in the lung (P < 0.05). In addition, the ratio of p-STAT3 to STAT3 protein in the rIL-22 group was significantly higher than that in the PBS group (P < 0.05). CONCLUSION

  16. Biomarkers for oxidative stress in acute lung injury induced in rabbits submitted to different strategies of mechanical ventilation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxidative damage has been said to play an important role in pulmonary injury, which is associated with the development and progression of acute respiratory distress syndrome (ARDS). We aimed to identify biomarkers to determine the oxidative stress in an animal model of acute lung injury (ALI) using ...

  17. Effects of a Soluble Epoxide Hydrolase Inhibitor on Lipopolysaccharide-Induced Acute Lung Injury in Mice

    PubMed Central

    Yang, Liu-Qing; Ma, Yong-Bo

    2016-01-01

    Objectives Inflammation plays a key role in the pathogenesis of acute lung injury (ALI). Soluble epoxide hydrolase (sEH) is suggested as a vital pharmacologic target for inflammation. In this study, we determined whether a sEH inhibitor, AUDA, exerts lung protection in lipopolysaccharide (LPS)-induced ALI in mice. Methods Male BALB/c mice were randomized to receive AUDA or vehicle intraperitoneal injection 4 h after LPS or phosphate buffered saline (PBS) intratracheal instillation. Samples were harvested 24 h post LPS or PBS administration. Results AUDA administration decreased the pulmonary levels of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α. Improvement of oxygenation and lung edema were observed in AUDA treated group. AUDA significantly inhibited sEH activity, and elevated epoxyeicosatrienoic acids (EETs) levels in lung tissues. Moreover, LPS induced the activation of nuclear factor (NF)-κB was markedly dampened in AUDA treated group. Conclusion Administration of AUDA after the onset of LPS-induced ALI increased pulmonary levels of EETs, and ameliorated lung injury. sEH is a potential pharmacologic target for ALI. PMID:27490848

  18. Pendrin, an anion exchanger on lung epithelial cells, could be a novel target for lipopolysaccharide-induced acute lung injury mice

    PubMed Central

    Jia, Chun-E; Jiang, Dingyuan; Dai, Huaping; Xiao, Fei; Wang, Chen

    2016-01-01

    Objective: The aim of this study is to evaluate the role of pendrin in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and to explore whether pendrin expression existing on alveolar cells. Methods: ALI C57BL/6 mice model induced by lipopolysaccharide (LPS) was established. The expression of pendrin in lung was analyzed by RT-PCR and western blotting methods, the changes of lung inflammatory parameters and pathology were observed, the cellular distribution of pendrin in the lung was determined using immunofluorescence. Statistical comparisons between groups were made by two-tailed Student’s t-test. Results: Enhanced expression of the slc26a4 gene and production of pendrin in lungs of LPS-induced ALI mice were confirmed. In comparison with vehicle-control mice, methazolamide treatment mitigated lung inflammatory parameters and pathology. IL-6 and MCP-1 in lung tissues and BALF in methazolamide-treated mice were statistically decreased. Methazolamide treatment had significant effect on the total protein concentration in the BALF and the ratio of lung wet/dry weight. The percentage of macrophages in the BALF was increased. There was a low expression of pendrin in ATII. Conclusions: Pendrin may be involved in pathological process of LPS-induced ALI. Inhibition of the pendrin function could be used to treat ALI. Airway epithelial cell may be a valuable therapeutic target for discovering and developing new drugs and/or new therapeutic strategies for the treatment of ALI/ARDS. PMID:27158384

  19. Neutrophil DNA contributes to the antielastase barrier during acute lung inflammation.

    PubMed

    Balloy, Viviane; Sallenave, Jean-Michel; Crestani, Bruno; Dehoux, Monique; Chignard, Michel

    2003-06-01

    During acute lung inflammation, the airspaces are invaded by circulating neutrophils. These may then injure tissues through the release of elastase. Different natural specific inhibitors such as alpha1-proteinase inhibitor, secretory leukocyte proteinase inhibitor, and elafin are nonetheless able to counteract the enzymatic activity of elastase. The present study was undertaken to assess the role of these different inhibitors in the intrinsic antielastase barrier during lipopolysaccharide-induced lung inflammation in mice. Upon intranasal administration of lipopolysaccharide to mice, the antielastase activity recovered from bronchoalveolar lavage fluids (BALF) increases progressively up to 48 h (7-fold) and returns to the basal level within 72 h. By contrast, when the same experiments are performed with neutropenic mice (pretreatment with an antigranulocyte antibody, or vinblastine), the increase is almost totally absent. Ultrafiltration of BALF through 100 kD cutoff membranes shows that the activity remains in the retentate, thus ruling out a role for native alpha1-proteinase inhibitor, secretory leukocyte proteinase inhibitor, and elafin. Gel filtration and fraction analysis show that the material eluted with a Mr of 600 kD. Agarose gel electrophoresis and ethidium bromide staining reveal that the activity corresponds to the presence a large amount of DNA. Interestingly, DNase treatment of the active fraction suppresses the antielastase activity. Analysis of BALF from patients with acute lung inflammation shows the presence of DNA with antielastase activity. We therefore concluded that during acute lung inflammation, the recruitment of neutrophils in the airspaces accounts for the increased presence of DNA, which in turn contributes to the antielastase barrier. PMID:12600833

  20. Bench-to-bedside review: Adenosine receptors – promising targets in acute lung injury?

    PubMed Central

    Schepp, Carsten P; Reutershan, Jörg

    2008-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening disorders that have substantial adverse effects on outcomes in critically ill patients. ALI/ARDS develops in response to pulmonary or extrapulmonary injury and is characterized by increased leakage from the pulmonary microvasculature and excessive infiltration of polymorphonuclear cells into the lung. Currently, no therapeutic strategies are available to control these fundamental pathophysiological processes in human ALI/ARDS. In a variety of animal models and experimental settings, the purine nucleoside adenosine has been demonstrated to regulate both endothelial barrier integrity and polymorphonuclear cell trafficking in the lung. Adenosine exerts its effects through four G-protein-coupled receptors (A1, A2A, A2B, and A3) that are expressed on leukocytes and nonhematopoietic cells, including endothelial and epithelial cells. Each type of adenosine receptor (AR) is characterized by a unique pharmacological and physiological profile. The development of selective AR agonists and antagonists, as well as the generation of gene-deficient mice, has contributed to a growing understanding of the cellular and molecular processes that are critically involved in the development of ALI/ARDS. Adenosine-dependent pathways are involved in both protective and proinflammatory effects, highlighting the need for a detailed characterization of the distinct pathways. This review summarizes current experimental observations on the role of adenosine signaling in the development of acute lung injury and illustrates that adenosine and ARs are promising targets that may be exploited in the development of innovative therapeutic strategies. PMID:18828873

  1. HIF1A Reduces Acute Lung Injury by Optimizing Carbohydrate Metabolism in the Alveolar Epithelium

    PubMed Central

    Bonney, Megan; Packard, Thomas; Han, Jun; Borchers, Christoph H.; Mariani, Thomas J.; Kominsky, Douglas J.; Mittelbronn, Michel; Eltzschig, Holger K.

    2013-01-01

    Background While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection. Methods and Findings To examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions—an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of 13C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A. Conclusions These studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung

  2. Enhanced Hsp70 expression protects against acute lung injury by modulating apoptotic pathways.

    PubMed

    Aschkenasy, Gabriella; Bromberg, Zohar; Raj, Nichelle; Deutschman, Clifford S; Weiss, Yoram G

    2011-01-01

    The Acute respiratory distress syndrome (ARDS) is a highly lethal inflammatory lung disorder. Apoptosis plays a key role in its pathogenesis. We showed that an adenovirus expressing the 70 kDa heat shock protein Hsp70 (AdHSP) protected against sepsis-induced lung injury. In this study we tested the hypothesis that AdHSP attenuates apoptosis in sepsis-induced lung injury. Sepsis was induced in rats via cecal ligation and double puncture (2CLP). At the time of 2CLP PBS, AdHSP or AdGFP (an adenoviral vector expressing green fluorescent protein) were injected into the tracheas of septic rats. 48 hours later, lungs were isolated. One lung was fixed for TUNEL staining and immunohistochemistry. The other was homogenized to isolate cytosolic and nuclear protein. Immunoblotting, gel filtration and co-immunoprecipitation were performed in these extracts. In separate experiments MLE-12 cells were incubated with medium, AdHSP or AdGFP. Cells were stimulated with TNFα. Cytosolic and nuclear proteins were isolated. These were subjected to immunoblotting, co-immunoprecipitation and a caspase-3 activity assay. TUNEL assay demonstrated that AdHSP reduced alveolar cell apoptosis. This was confirmed by immunohistochemical detection of caspase 3 abundance. In lung isolated from septic animals, immunoblotting, co-immunoprecipitation and gel filtration studies revealed an increase in cytoplasmic complexes containing caspases 3, 8 and 9. AdHSP disrupted these complexes. We propose that Hsp70 impairs apoptotic cellular pathways via interactions with caspases. Disruption of large complexes resulted in stabilization of lower molecular weight complexes, thereby, reducing nuclear caspase-3. Prevention of apoptosis in lung injury may preserve alveolar cells and aid in recovery. PMID:22132083

  3. Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation.

    PubMed

    Sunil, Vasanthi R; Vayas, Kinal N; Cervelli, Jessica A; Malaviya, Rama; Hall, LeRoy; Massa, Christopher B; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L

    2014-08-01

    Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (150-174 g; 8-10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histopathological changes in the lung within 3d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2(+) and MMP-9(+)), and anti-inflammatory/wound repair (CD163+ and Gal-3(+)) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3(+) macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants. PMID:24886962

  4. Pulmonary natural killer T cells play an essential role in mediating hyperoxic acute lung injury.

    PubMed

    Nowak-Machen, Martina; Schmelzle, Moritz; Hanidziar, Dusan; Junger, Wolfgang; Exley, Mark; Otterbein, Leo; Wu, Yan; Csizmadia, Eva; Doherty, Glen; Sitkovsky, Michail; Robson, Simon C

    2013-05-01

    Critically ill patients are routinely exposed to high concentrations of supplemental oxygen for prolonged periods of time, which can be life-saving in the short term, but such exposure also causes severe lung injury and increases mortality. To address this therapeutic dilemma, we studied the mechanisms of the tissue-damaging effects of oxygen in mice. We show that pulmonary invariant natural killer T (iNKT) cells are unexpectedly crucial in the development of acute oxygen-induced lung injury. iNKT cells express high concentrations of the ectonucleotidase CD39, which regulates their state of activation. Both iNKT cell-deficient (Jα18(-/-)) and CD39-null mice tolerate hyperoxia, compared with wild-type control mice that exhibit severe lung injury. An adoptive transfer of wild-type iNKT cells into Jα18(-/-) mice results in hyperoxic lung injury, whereas the transfer of CD39-null iNKT cells does not. Pulmonary iNKT cell activation and proliferation are modulated by ATP-dependent purinergic signaling responses. Hyperoxic lung injury can be induced by selective P2X7-receptor blockade in CD39-null mice. Our data indicate that iNKT cells are involved in the pathogenesis of hyperoxic lung injury, and that tissue protection can be mediated through ATP-induced P2X7 receptor signaling, resulting in iNKT cell death. In conclusion, our data suggest that iNKT cells and purinergic signaling should be evaluated as potential novel therapeutic targets to prevent hyperoxic lung injury. PMID:23349052

  5. Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury.

    PubMed

    Yin, Jun; Michalick, Laura; Tang, Christine; Tabuchi, Arata; Goldenberg, Neil; Dan, Qinghong; Awwad, Khader; Wang, Liming; Erfinanda, Lasti; Nouailles, Geraldine; Witzenrath, Martin; Vogelzang, Alexis; Lv, Lu; Lee, Warren L; Zhang, Haibo; Rotstein, Ori; Kapus, Andras; Szaszi, Katalin; Fleming, Ingrid; Liedtke, Wolfgang B; Kuppe, Hermann; Kuebler, Wolfgang M

    2016-03-01

    The cation channel transient receptor potential vanilloid (TRPV) 4 is expressed in endothelial and immune cells; however, its role in acute lung injury (ALI) is unclear. The functional relevance of TRPV4 was assessed in vivo, in isolated murine lungs, and in isolated neutrophils. Genetic deficiency of TRPV4 attenuated the functional, histological, and inflammatory hallmarks of acid-induced ALI. Similar protection was obtained with prophylactic administration of the TRPV4 inhibitor, GSK2193874; however, therapeutic administration of the TRPV4 inhibitor, HC-067047, after ALI induction had no beneficial effect. In isolated lungs, platelet-activating factor (PAF) increased vascular permeability in lungs perfused with trpv4(+/+) more than with trpv4(-/-) blood, independent of lung genotype, suggesting a contribution of TRPV4 on blood cells to lung vascular barrier failure. In neutrophils, TRPV4 inhibition or deficiency attenuated the PAF-induced increase in intracellular calcium. PAF induced formation of epoxyeicosatrienoic acids by neutrophils, which, in turn, stimulated TRPV4-dependent Ca(2+) signaling, whereas inhibition of epoxyeicosatrienoic acid formation inhibited the Ca(2+) response to PAF. TRPV4 deficiency prevented neutrophil responses to proinflammatory stimuli, including the formation of reactive oxygen species, neutrophil adhesion, and chemotaxis, putatively due to reduced activation of Rac. In chimeric mice, however, the majority of protective effects in acid-induced ALI were attributable to genetic deficiency of TRPV4 in parenchymal tissue, whereas TRPV4 deficiency in circulating blood cells primarily reduced lung myeloperoxidase activity. Our findings identify TRPV4 as novel regulator of neutrophil activation and suggest contributions of both parenchymal and neutrophilic TRPV4 in the pathophysiology of ALI. PMID:26222277

  6. Bedside lung ultrasound in the evaluation of acute decompensated heart failure.

    PubMed

    Leidi, Federica; Casella, Francesco; Cogliati, Chiara

    2016-06-01

    Dyspnea is a common presenting complaint in the emergency department (ED) and a leading cause of hospitalization in intensive care unit (ICU) and medical wards. Ultrasound (US) has traditionally been considered inadequate to explore the aerated lung. However, in the past 15 years LUS gained broader application, at least in part thanks to the interpretation of the artefacts generated by the interaction of US and lung structures/content. The total reflection of US beam occurring at the pleural level determines the artefactual image of the aerated lung: an homogenous 'foggy-like' picture under the pleural line. As the air content of the lungs decreases due to interstitial imbibition, deposition of collagen or presence of blood, vertical artefacts -arising from the pleural line and moving synchronously with the respiration- called B-lines appear. Multiple and bilateral B-lines identify the alveolar-interstitial syndrome (AIS). The most common cause of AIS is the wet lung: the more the congestion burden, the more the extent of the B-lines, which become confluent until the so-called white lung in case of pulmonary edema. Many studies showed a higher accuracy of LUS in diagnosing acute decompensated heart failure (ADHF) as compared to chest X-ray As recently shown, the integration of LUS to clinical assessment allow to differentiate cardiogenic dyspnea with sensitivity and specificity greater than 95 %. Moreover, LUS can easily detect pleural effusion -frequently present in ADHF-appearing as an anechoic area in the recumbent area of the thorax, delimited inferiorly by the diaphragmatic dome and superiorly by the aerated lung. PMID:26885846

  7. [From isoflurane to perfluorohexane? Perfluorocarbons--therapeutic strategies in acute lung failure].

    PubMed

    Ragaller, M; Bleyl, J U; Koch, T; Albrecht, D M

    2000-04-01

    The introduction of Perfluorochemicals into medicine and especially into the treatment of severe lung injury is a fascinating scientific task. Many recall the famous experiments from Clark et al. in 1966 when he demonstrated "liquidventilation with perfluorocarbons" in the mammal species for the first time. After this hallmark, perfluorocarbons were subsequently introduced in research of acute lung injury by the techniques of Total- and Partial-Liquid-Ventilation (TLV; PLV). Perfluorocarbons (saturated organofluorids) have unique chemical and physical properties which made them attractive substances for intraalveolar application. The strong C-F bindings in the perfluorocarbon molecules are responsible for their chemical stability, biochemical inertness, high capacity to dissolve respiratory gases, low surface tension and high vapor pressures. Furthermore, the high density of the PFC lead to radio-opacity and their distribution to dependent lung areas. The efficacy of PFC liquid, applied by TLV/PLV has been demonstrated in numerous animal studies using different models of acute lung injury. Currently, several mechanisms of action of perfluorocarbon fluids in acute lung injury are discussed: recruitment of atelectatic alveoli, prevention of endexpiratory collapse of alveoli ("liquid PEEP"), redistribution of perfusion, oxygen transport, surfactant like effects and decrease of inflammation. Since total liquid ventilation has been used only in experimental models of lung injury, partial liquid ventilation has been introduced successfully into clinical trials (phase I-II). However, the results of the first randomised, controlled study of PLV in 90 adult patients suffering from severe respiratory failure (ALI/ARDS) showed no differences between PLV and conventional treatment. Furthermore, the instillation of relatively large amounts of liquid into the lungs poses several technical challenges and may be associated with complications such as liquithoraces, pneumothoraces

  8. C1P Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Preventing NF-κB Activation in Neutrophils.

    PubMed

    Baudiß, Kristin; de Paula Vieira, Rodolfo; Cicko, Sanja; Ayata, Korcan; Hossfeld, Madelon; Ehrat, Nicolas; Gómez-Muñoz, Antonio; Eltzschig, Holger K; Idzko, Marco

    2016-03-01

    Recently, ceramide-1-phosphate (C1P) has been shown to modulate acute inflammatory events. Acute lung injury (Arnalich et al. 2000. Infect. Immun. 68: 1942-1945) is characterized by rapid alveolar injury, lung inflammation, induced cytokine production, neutrophil accumulation, and vascular leakage leading to lung edema. The aim of this study was to investigate the role of C1P during LPS-induced acute lung injury in mice. To evaluate the effect of C1P, we used a prophylactic and therapeutic LPS-induced ALI model in C57BL/6 male mice. Our studies revealed that intrapulmonary application of C1P before (prophylactic) or 24 h after (therapeutic) LPS instillation decreased neutrophil trafficking to the lung, proinflammatory cytokine levels in bronchoalveolar lavage, and alveolar capillary leakage. Mechanistically, C1P inhibited the LPS-triggered NF-κB levels in lung tissue in vivo. In addition, ex vivo experiments revealed that C1P also attenuates LPS-induced NF-κB phosphorylation and IL-8 production in human neutrophils. These results indicate C1P playing a role in dampening LPS-induced acute lung inflammation and suggest that C1P could be a valuable candidate for treatment of ALI. PMID:26800872

  9. A NOVEL WEARABLE PUMP-LUNG DEVICE: IN-VITRO AND ACUTE IN-VIVO STUDY

    PubMed Central

    Zhang, Tao; Wei, Xufeng; Bianchi, Giacomo; Wong, Philip M.; Biancucci, Brian; Griffith, Bartley P.; Wu, Zhongjun J.

    2011-01-01

    Background To provide long-term ambulatory cardiopulmonary and respiratory support for adult patients, a novel wearable artificial pump-lung device has been developed. The design features, in-vitro and acute in-vivo performance of this device are reported in this paper. Methods This device features a uniquely designed hollow fiber membrane bundle integrated with a magnetically levitated impeller together to form one ultra-compact pump-lung device, which can be placed like current paracorporeal ventricular assist devices to allow ambulatory support. The device is 117 mm in length and 89 mm in diameter and has a priming volume of 115 ml. In-vitro hydrodynamic, gas transfer and biocompatibility experiments were carried out in mock flow loops using ovine blood. Acute in-vivo characterization was conducted in ovine by surgically implanting the device between right atrium and pulmonary artery. Results The in-vitro results showed that the device with a membrane surface area of 0.8 m2 was capable of pumping blood from 1 to 4 L/min against a wide range of pressures and transferring oxygen at a rate of up to 180 ml/min at a blood flow of 3.5 L/min. Standard hemolysis tests demonstrated low hemolysis at the targeted operating condition. The acute in-vivo results also confirmed that the device can provide sufficient oxygen transfer with excellent biocompatibility. Conclusions Base on the in-vitro and acute in-vivo study, this highly integrated wearable pump-lung device can provide efficient respiratory support with good biocompatibility and it is ready for long-term evaluation. PMID:22014451

  10. Endotoxin-induced acute lung injury is enhanced in rats with spontaneous hypertension.

    PubMed

    Liu, Demeral D; Hsu, Yung Hsiang; Chen, Hsing I

    2007-01-01

    1. Acute lung injury (ALI), or acute respiratory distress syndrome, is a major cause of mortality in endotoxaemia. The present study tested whether the endotoxaemia-induced changes and associated ALI were enhanced in rats with established hypertension and to examine the possible mechanisms involved. 2. Fifty spontaneously hypertensive rats (SHR) and the same number of normotensive Wistar Kyoto (WKY) rats, aged 12-15 weeks, were used. The experiments were performed in conscious, unanaesthetized rats. Endotoxaemia was produced by intravenous lipopolysaccharide (LPS; 10 mg/kg). N(G)-Nitro-L-arginine methyl ester (L-NAME; 10 mg/kg, i.v.), L-N(6)-(1-iminoethyl)-lysine (L-Nil; 5 mg/kg, i.v.) and 3-morpholinosydnonimine (SIN-1; 5 mg/kg, i.v.) were given 5 min before LPS to observe the effects of nitric oxide synthase (NOS) inhibition and nitric oxide (NO) donation. 3. We monitored arterial pressure and heart rate and evaluated ALI by determining the lung weight/bodyweight ratio, lung weight gain, leakage of Evans blue dye, the protein concentration in bronchoalveolar lavage and histopathological examination. Plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines, including tumour necrosis factor-alpha and interleukin-1beta, and lung tissue cGMP were determined. Expression of mRNA for inducible and endothelial NOS was examined using reverse transcription-polymerase chain reaction. 4. Lipopolysaccharide caused systemic hypotension, ALI and increases in plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines and lung cGMP content. The LPS-induced changes were greater in SHR than in WKY rats. Pretreatment with L-NAME or L-Nil attenuated, whereas the NO donor SIN-1 aggravated, the endotoxin-induced changes. 5. In conclusion, rats with genetic hypertension are more susceptible to endotoxaemia and this results in a greater extent of ALI compared with normotensive WKY rats. PMID:17201737

  11. Acute Inhalation Exposure to Vaporized Methamphetamine Causes Lung Injury in Mice

    PubMed Central

    Wells, Sandra M.; Buford, Mary C.; Braseth, Sarah N.; Hutchison, James D.; Holian, Andrij

    2009-01-01

    Methamphetamine (MA) is currently the most widespread illegally used stimulant in the United States. Use of MA by smoking is the fastest growing mode of administration, which increases concerns about potential pulmonary and other medical complications. A murine exposure system was developed to study the pulmonary affects of inhaled MA. Mice were exposed to 25–100 mg vaporized MA and assessments were made 3 h following initiation of exposure to model acute lung injury. Inhalation of MA vapor resulted in dose-dependent increases in MA plasma levels that were in the range of those experienced by MA users. At the highest MA dose, histological changes were observed in the lung and small but significant increases in lung wet weight to body weight ratios (5.656 ± 0.176 mg/g for the controls vs. 6.706± 0.135 mg/g for the 100 mg MA-exposed mice) were found. In addition, there was 53% increase in total protein in bronchoalveolar lavage (BAL) fluid, greater than 20% increase in albumin levels in the BAL fluid, greater than 2.5-fold increase in lactate dehydrogenase levels in the BAL fluid, and reduced total BAL cell numbers (approximately 77% of controls). Levels of the early response cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 were dose-dependently increased in BAL fluid of MA-exposed mice. Exposure to 100 mg MA significantly increased free radical generation in the BAL cells to 107–146% of controls and to approximately 135% of the controls in lung tissue in situ. Together, these data show that acute inhalation exposure to relevant doses of volatilized MA is associated with elevated free radical formation and significant lung injury. PMID:18645723

  12. Soyasaponin Ab inhibits lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Lin, Jing; Cheng, Yanwen; Wang, Tao; Tang, Lihua; Sun, Yan; Lu, Xiuyun; Yu, Huimin

    2016-01-01

    Soyasaponin Ab (SA) has been reported to have anti-inflammatory effect. However, the effects of SA on lipopolysaccharide (LPS)-induced acute lung injury (ALI) have not been reported. The aim of this study was to investigate the anti-inflammatory effects of SA on LPS-induced ALI and clarify the possible mechanism. The mice were stimulated with LPS to induce ALI. SA was given 1h after LPS treatment. 12h later, lung tissues were collected to assess pathological changes and edema. Bronchoalveolar lavage fluid (BALF) was collected to assess inflammatory cytokines and nitric oxide (NO) production. In vitro, mice alveolar macrophages were used to investigate the anti-inflammatory mechanism of SA. Our results showed that SA attenuated LPS-induced lung pathological changes, edema, the expression of cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in lung tissues, as well as TNF-α, IL-6, IL-1β, and NO production in mice. Meanwhile, SA up-regulated the activities of superoxide dismutase (SOD) and catalase decreased by LPS in mice. SA also inhibited LPS-induced TNF-α, IL-6 and IL-1β production as well as NF-κB activation in alveolar macrophages. Furthermore, SA could activate Liver X Receptor Alpha (LXRα) and knockdown of LXRα by RNAi abrogated the anti-inflammatory effects of SA. In conclusion, the current study demonstrated that SA exhibited protective effects against LPS-induced acute lung injury and the possible mechanism was involved in activating LXRα, thereby inhibiting LPS-induced inflammatory response. PMID:26672918

  13. Protective effect of taraxasterol on acute lung injury induced by lipopolysaccharide in mice.

    PubMed

    San, Zhihao; Fu, Yunhe; Li, Wei; Zhou, Ershun; Li, Yimeng; Song, Xiaojing; Wang, Tiancheng; Tian, Yuan; Wei, Zhengkai; Yao, Minjun; Cao, Yongguo; Zhang, Naisheng

    2014-04-01

    Taraxasterol, a pentacyclic-triterpene isolated from Taraxacum officinale, has been reported to have potent anti-inflammatory properties. However, the effect of taraxasterol on lipopolysaccharide (LPS)-induced mice acute lung injury has not been investigated. The aims of this study were to investigate whether taraxasterol could ameliorate the inflammation response in LPS-induced acute lung injury and to clarify the possible mechanism. Male BALB/c mice were pretreated with taraxasterol 1h before intranasal instillation of LPS. 7h after LPS administration, the myeloperoxidase (MPO) in lung tissues, lung wet/dry ratio and inflammatory cells in the bronchoalveolar lavage fluid (BALF) were detected. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) in the BALF were measured by ELISA. The extent of phosphorylation of IκB-α, p65 NF-κB, p46-p54 JNK, p42-p44 ERK, and p38 were determined by western blotting. The results showed that taraxasterol attenuated the infiltration of inflammatory cells, the activity of myeloperoxidase (MPO), lung wet/dry ratio, and the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in a dose-dependent manner. Additionally, western blotting results showed that taraxasterol inhibited the phosphorylation of IκB-α, p65 NF-κB, p46-p54 JNK, p42-p44 ERK, and p38 caused by LPS. Our data suggest that anti-inflammatory effects of taraxasterol against the LPS-induced ALI may be due to its ability of inhibition of the NF-κB and MAPK signaling pathways. PMID:24548765

  14. Biphasic positive airway pressure minimizes biological impact on lung tissue in mild acute lung injury independent of etiology

    PubMed Central

    2013-01-01

    Introduction Biphasic positive airway pressure (BIVENT) is a partial support mode that employs pressure-controlled, time-cycled ventilation set at two levels of continuous positive airway pressure with unrestricted spontaneous breathing. BIVENT can modulate inspiratory effort by modifying the frequency of controlled breaths. Nevertheless, the optimal amount of inspiratory effort to improve respiratory function while minimizing ventilator-associated lung injury during partial ventilatory assistance has not been determined. Furthermore, it is unclear whether the effects of partial ventilatory support depend on acute lung injury (ALI) etiology. This study aimed to investigate the impact of spontaneous and time-cycled control breaths during BIVENT on the lung and diaphragm in experimental pulmonary (p) and extrapulmonary (exp) ALI. Methods This was a prospective, randomized, controlled experimental study of 60 adult male Wistar rats. Mild ALI was induced by Escherichia coli lipopolysaccharide either intratracheally (ALIp) or intraperitoneally (ALIexp). After 24 hours, animals were anesthetized and further randomized as follows: (1) pressure-controlled ventilation (PCV) with tidal volume (Vt) = 6 ml/kg, respiratory rate = 100 breaths/min, PEEP = 5 cmH2O, and inspiratory-to-expiratory ratio (I:E) = 1:2; or (2) BIVENT with three spontaneous and time-cycled control breath modes (100, 75, and 50 breaths/min). BIVENT was set with two levels of CPAP (Phigh = 10 cmH2O and Plow = 5 cmH2O). Inspiratory time was kept constant (Thigh = 0.3 s). Results BIVENT was associated with reduced markers of inflammation, apoptosis, fibrogenesis, and epithelial and endothelial cell damage in lung tissue in both ALI models when compared to PCV. The inspiratory effort during spontaneous breaths increased during BIVENT-50 in both ALI models. In ALIp, alveolar collapse was higher in BIVENT-100 than PCV, but decreased during BIVENT-50, and diaphragmatic injury was lower during BIVENT-50 compared

  15. The adenosine 2A receptor agonist GW328267C improves lung function after acute lung injury in rats.

    PubMed

    Folkesson, Hans G; Kuzenko, Stephanie R; Lipson, David A; Matthay, Michael A; Simmons, Mark A

    2012-08-01

    There is a significant unmet need for treatments of patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). The primary mechanism that leads to resolution of alveolar and pulmonary edema is active vectorial Na(+) and Cl(-) transport across the alveolar epithelium. Several studies have suggested a role for adenosine receptors in regulating this fluid transport in the lung. Furthermore, these studies point to the A(2A) subtype of adenosine receptor (A(2A)R) as playing a role to enhance fluid transport, suggesting that activation of the A(2A)R may enhance alveolar fluid clearance (AFC). The current studies test the potential therapeutic value of the A(2A)R agonist GW328267C to accelerate resolution of alveolar edema and ALI/ARDS in rats. GW328267C, at concentrations of 10(-5) M to 10(-3) M, instilled into the airspaces, increased AFC in control animals. GW328267C did not increase AFC beyond that produced by maximal β-adrenergic stimulation. The effect of GW328267C was inhibited by amiloride but was not affected by cystic fibrosis transmembrane conductance regulator inhibition. The drug was tested in three models of ALI, HCl instillation 1 h, LPS instillation 16 h, and live Escherichia coli instillation 2 h before GW328267C instillation. After either type of injury, GW328267C (10(-4) M) decreased pulmonary edema formation and restored AFC, measured 1 h after GW328267C instillation. These findings show that GW328267C has beneficial effects in experimental models of ALI and may be a useful agent for treating patients with ALI or prophylactically to prevent ALI. PMID:22659881

  16. Extravascular lung water monitoring of renal replacement therapy in lung water scavenging for septic acute kidney injury

    PubMed Central

    Liu, Han; Liu, Ying; Sun, Jia-Kui; Xu, Qiao-Lian; Yan, Ying; Chen, Yong-Ming; Hong, Liang; Xu, Huan

    2015-01-01

    This study aims to investigate the extravascular lung water index (EVLWI) in lung water scavenging of sepsis patients with acute kidney injury (AKI) by renal replacement therapy (RRT). 57 septic acute kidney injury patients with EVLWI > 7 ml/kg were selected and randomly divided into two groups: the treatment group with continued RRT for 24 h per day, the control group with RRT for ≤8 h per day. Fluid resuscitation and RRT were performed simultaneously. After fluid resuscitation, EVLWI, hemodynamics, oxygenation index, blood lactate, and intensive care unit (ICU) stay were determined. The values of EVLWI, pulmonary vascular permeability index (PVPI), and blood lactate decreased and the intrathoracic blood volume index (ITBVI) increased significantly at 24 h, 48 h and 72 h, after RRT, compared with those before RRT in the two groups (P < 0.05). The values of EVLWI at 48 h and 72 h after RRT in the treatment group were significantly lower than that in the control group (P < 0.05). The cardiac index (CI) at 48 h and 72 h after RRT in the treatment group was significantly higher than that before RRT (P < 0.05). The values of PVPI, ITBVI, CI, blood lactate, transcutaneous oxygen saturation pulse (SPO2), oxygenation index (PO2/FiO2) and arterial oxygen (PO2) before and 24 h, 48 h, and 72 h after RRT. The 28d mortality had no significant difference in the two groups (P > 0.05). The average ICU stay for the treatment group was significantly shorter than that of the control group (P < 0.05). EVLWI monitoring of septic patients with AKI in RRT time had clinical reference value. PMID:26770515

  17. Enteral Omega-3 Fatty Acid, γ-Linolenic Acid, and Antioxidant Supplementation in Acute Lung Injury

    PubMed Central

    Rice, Todd W.; Wheeler, Arthur P.; Thompson, B. Taylor; deBoisblanc, Bennett P.; Steingrub, Jay; Rock, Peter

    2013-01-01

    Context The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with γ-linolenic acid and antioxidants, may modulate systemic inflammatory response and improve oxygenation and outcomes in patients with acute lung injury. Objective To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28. Design, Setting, and Participants The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up. Interventions Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement. Main Outcome Measure Ventilator-free days to study day 28. Results The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vs 17.2; P=.02) (difference, -3.2 [95% CI, -5.8 to -0.7]) and intensive care unit-free days (14.0 vs 16.7; P=.04). Patients in the n-3 group also had fewer nonpulmonary organ failure-free days (12.3 vs 15.5; P=.02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P=.054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P=.11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P=.001). Conclusions Twice-daily enteral supplementation of n-3

  18. Imbalance of Th17/Tregs in rats with smoke inhalation-induced acute lung injury.

    PubMed

    Zhang, Fan; Li, Mian-yang; Lan, Ya-ting; Wang, Cheng-bin

    2016-01-01

    T helper (Th) 17 cells and CD4(+) CD25(+) regulatory T (Treg) cells are supposed to be critically involved in regulating autoimmune and inflammatory diseases. The aim of this study was to investigate the Th17/Treg pattern in rats with gunpowder smog-induced acute lung injury. Wistar rats were equally randomized to three groups: normal control group, ALI 6 h group (smoke inhalation for 6 h) and ALI 24 h group (smoke inhalation for 24 h). We observed changes in cell counting in bronchoalveolar lavage fluid (BALF), alveolar-capillary membrane permeability and lung tissue pathology. Moreover, rats in ALI 6 h and ALI 24 h group showed increased expression of Th17 cell and related cytokines (IL-17 A, IL-6, TGF-β and IL-23). Meanwhile, Treg prevalence and related cytokines (IL-10, IL-2 and IL-35) were decreased. Consequently, the ratio of Th17/Treg was higher after smoke inhalation. Additionally, Th1 cell decreased while Th2 cell increased at 6 h and 24 h after smoke inhalation. In conclusion, Th17/Treg imbalance exists in rats with smoke inhalation-induced acute lung injury, suggesting its potential role in the pathogenesis of this disease. PMID:26884314

  19. Imbalance of Th17/Tregs in rats with smoke inhalation-induced acute lung injury

    PubMed Central

    Zhang, Fan; Li, Mian-yang; Lan, Ya-ting; Wang, Cheng-bin

    2016-01-01

    T helper (Th) 17 cells and CD4+ CD25+ regulatory T (Treg) cells are supposed to be critically involved in regulating autoimmune and inflammatory diseases. The aim of this study was to investigate the Th17/Treg pattern in rats with gunpowder smog-induced acute lung injury. Wistar rats were equally randomized to three groups: normal control group, ALI 6 h group (smoke inhalation for 6 h) and ALI 24 h group (smoke inhalation for 24 h). We observed changes in cell counting in bronchoalveolar lavage fluid (BALF), alveolar-capillary membrane permeability and lung tissue pathology. Moreover, rats in ALI 6 h and ALI 24 h group showed increased expression of Th17 cell and related cytokines (IL-17 A, IL-6, TGF-β and IL-23). Meanwhile, Treg prevalence and related cytokines (IL-10, IL-2 and IL-35) were decreased. Consequently, the ratio of Th17/Treg was higher after smoke inhalation. Additionally, Th1 cell decreased while Th2 cell increased at 6 h and 24 h after smoke inhalation. In conclusion, Th17/Treg imbalance exists in rats with smoke inhalation-induced acute lung injury, suggesting its potential role in the pathogenesis of this disease. PMID:26884314

  20. Enforced expression of miR-125b attenuates LPS-induced acute lung injury.

    PubMed

    Guo, Zhongliang; Gu, Yutong; Wang, Chunhong; Zhang, Jie; Shan, Shan; Gu, Xia; Wang, Kailing; Han, Yang; Ren, Tao

    2014-11-01

    The acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) in humans, is a leading cause of morbidity and mortality in critically ill patients. Despite decades of research, few therapeutic strategies for clinical ARDS have emerged. Recent evidence implicated a potential role of miR-125b in development of ALI. Here we evaluated the miR-125b-based strategy in treatment of ARDS using the murine model of lipopolysaccharide (LPS)-induced ALI. We found that up-regulation of miR-125b expression maintained the body weight and survival of ALI mice, and significantly reduced LPS-induced pulmonary inflammation as reflected by reductions in total cell and neutrophil counts, proinflammatory cytokines, as well as chemokines in BAL fluid. Further, enforced expression of miR-125b resulted in remarkable reversal of LPS-induced increases in lung permeability as assessed by reductions in total protein, albumin and IgM in BAL fluid, and ameliorated the histopathology changes of lung in LPS-induced ALI mice. Of interest, serum miR-125b expression was also decreased and inversely correlated with the disease severity in patients with ARDS. Our findings strongly demonstrated that enforced expression of miR-125b could effectively ameliorate the LPS-induced ALI, suggesting a potential application for miR-125b-based therapy to treat clinical ARDS. PMID:25004393

  1. Nogo-B protects mice against lipopolysaccharide-induced acute lung injury

    PubMed Central

    Xu, Wujian; Zhu, Ying; Ning, Yunye; Dong, Yuchao; Huang, Haidong; Zhang, Wei; Sun, Qinying; Li, Qiang

    2015-01-01

    Nogo-B, a member of the reticulon 4 protein family, plays a critical role in tissue repair and acute inflammation. Its role in acute lung injury (ALI) remains unclear. Here, we assessed the function of Nogo-B during tissue injury in a lipopolysaccharide (LPS)-induced ALI mouse model. We found that pulmonary Nogo-B was significantly repressed after LPS instillation in C57BL/6 mice. Over-expression of pulmonary Nogo-B using an adenovirus vector carrying the Nogo-B-RFP-3flag gene (Ad-Nogo-B) significantly prolonged the survival of mice challenged with a lethal dose of LPS. The Ad-Nogo-B-treated mice also had less severe lung injury, less alveolar protein exudation, and a higher number of macrophages but less neutrophil infiltration compared with Ad-RFP-treated mice. Interestingly, microarray analysis showed that the Ad-Nogo-B-treated mice had different gene expression profiles compared with the controls and the prominent expression of genes related to wound healing and the humoral immune response after LPS induction. Of the 49 differently expressed genes, we found that the expression of PTX3 was significantly up-regulated following Nogo-B over-expression as observed in lung tissues and RAW264.7 cells. In conclusion, Nogo-B plays a protective role against LPS-induced ALI, and this effect might be exerted through the modulation of alveolar macrophage recruitment and PTX3 production. PMID:26174362

  2. Potential Effects of Medicinal Plants and Secondary Metabolites on Acute Lung Injury

    PubMed Central

    Cornélio Favarin, Daniely; Robison de Oliveira, Jhony; Jose Freire de Oliveira, Carlo; de Paula Rogerio, Alexandre

    2013-01-01

    Acute lung injury (ALI) is a life-threatening syndrome that causes high morbidity and mortality worldwide. ALI is characterized by increased permeability of the alveolar-capillary membrane, edema, uncontrolled neutrophils migration to the lung, and diffuse alveolar damage, leading to acute hypoxemic respiratory failure. Although corticosteroids remain the mainstay of ALI treatment, they cause significant side effects. Agents of natural origin, such as medicinal plants and their secondary metabolites, mainly those with very few side effects, could be excellent alternatives for ALI treatment. Several studies, including our own, have demonstrated that plant extracts and/or secondary metabolites isolated from them reduce most ALI phenotypes in experimental animal models, including neutrophil recruitment to the lung, the production of pro-inflammatory cytokines and chemokines, edema, and vascular permeability. In this review, we summarized these studies and described the anti-inflammatory activity of various plant extracts, such as Ginkgo biloba and Punica granatum, and such secondary metabolites as epigallocatechin-3-gallate and ellagic acid. In addition, we highlight the medical potential of these extracts and plant-derived compounds for treating of ALI. PMID:24224172

  3. ROS-Mediated NLRP3 Inflammasome Activity Is Essential for Burn-Induced Acute Lung Injury

    PubMed Central

    Han, Shichao; Cai, Weixia; Yang, Xuekang; Jia, Yanhui; Zheng, Zhao; Wang, Hongtao; Li, Jun; Li, Yan; Gao, Jianxin; Fan, Lei; Hu, Dahai

    2015-01-01

    The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO) activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF). In the in vitro experiments, we used AMs (alveolar macrophages) challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS) production. The use of ROS scavenger N-acetylcysteine (NAC) partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI. PMID:26576075

  4. Adult stem cells for acute lung injury: remaining questions and concerns.

    PubMed

    Zhu, Ying-Gang; Hao, Qi; Monsel, Antoine; Feng, Xiao-Mei; Lee, Jae-Woo

    2013-07-01

    Acute lung injury (ALI) or acute respiratory distress syndrome remains a major cause of morbidity and mortality in hospitalized patients. The pathophysiology of ALI involves complex interactions between the inciting event, such as pneumonia, sepsis or aspiration, and the host immune response resulting in lung protein permeability, impaired resolution of pulmonary oedema, an intense inflammatory response in the injured alveolus and hypoxemia. In multiple preclinical studies, adult stem cells have been shown to be therapeutic due to both the ability to mitigate injury and inflammation through paracrine mechanisms and perhaps to regenerate tissue by virtue of their multi-potency. These characteristics have stimulated intensive research efforts to explore the possibility of using stem or progenitor cells for the treatment of lung injury. A variety of stem or progenitor cells have been isolated, characterized and tested experimentally in preclinical animal models of ALI. However, questions remain concerning the optimal dose, route and the adult stem or progenitor cell to use. Here, the current mechanisms underlying the therapeutic effect of stem cells in ALI as well as the questions that will arise as clinical trials for ALI are planned are reviewed. PMID:23578018

  5. Blockade of Interleukin-17 Restrains the Development of Acute Lung Injury.

    PubMed

    Li, Q; Gu, Y; Tu, Q; Wang, K; Gu, X; Ren, T

    2016-03-01

    The acute respiratory distress syndrome (ARDS), a clinical complication of severe acute lung injury (ALI) in humans, is a leading cause of morbidity and mortality in critically ill patients. Here, we explored the association between IL-17 and development of ALI using LPS-induced murine model. We found that IL-17 level was elevated in bronchoalveolar lavage (BAL) fluid of ALI mice. Upregulation of IL-17 resulted in increased severity of ALI as evidenced by decreased body weight and survival rate, elevated level of total protein and albumin in BAL fluid, as well as more apparent histopathology changes of lung. Induction of ALI was impaired in IL-17-deficient mice. Management of IL-17 could modulate LPS-induced pulmonary inflammation, as reflected by the total cell and neutrophil counts, proinflammatory cytokines, as well as chemokines in BAL fluid. Of note, blockade of IL-17 effectively inhibited the lung inflammation and alleviated ALI severity. Finally, we confirmed the clinical relevance and found that IL-17 expression was elevated and associated with the disease severity in patients with ARDS. In essence, IL-17 was crucial for development of ALI, suggesting a potential application for IL-17-based therapy in clinical practice. PMID:26709006

  6. Cardiac Physiologic and Genetic Predictors of Hyperoxia-Induced Acute Lung Injury in Mice

    PubMed Central

    Cho, Hye-Youn; Miller-DeGraff, Laura; Walker, Christopher; Clark, James A.; Myers, Page H.; Rouse, D. Clay; Kleeberger, Steven R.

    2012-01-01

    Exposure of mice to hyperoxia produces pulmonary toxicity similar to acute lung injury/acute respiratory distress syndrome, but little is known about the interactions within the cardiopulmonary system. This study was designed to characterize the cardiopulmonary response to hyperoxia, and to identify candidate susceptibility genes in mice. Electrocardiogram and ventilatory data were recorded continuously from 4 inbred and 29 recombinant inbred strains during 96 hours of hyperoxia (100% oxygen). Genome-wide linkage analysis was performed in 27 recombinant inbred strains against response time indices (TIs) calculated from each cardiac phenotype. Reductions in minute ventilation, heart rate (HR), low-frequency (LF) HR variability (HRV), high-frequency HRV, and total power HRV were found in all mice during hyperoxia exposure, but the lag time before these changes began was strain dependent. Significant (chromosome 9) or suggestive (chromosomes 3 and 5) quantitative trait loci were identified for the HRTI and LFTI. Functional polymorphisms in several candidate susceptibility genes were identified within the quantitative trait loci and were associated with hyperoxia susceptibility. This is the first study to report highly significant interstrain variation in hyperoxia-induced changes in minute ventilation, HR, and HRV, and to identify polymorphisms in candidate susceptibility genes that associate with cardiac responses. Results indicate that changes in HR and LF HRV could be important predictors of subsequent adverse outcome during hyperoxia exposure, specifically the pathogenesis of acute lung injury. Understanding the genetic mechanisms of these responses may have significant diagnostic clinical value. PMID:22052878

  7. The role of C5a in acute lung injury induced by highly pathogenic viral infections

    PubMed Central

    Wang, Renxi; Xiao, He; Guo, Renfeng; Li, Yan; Shen, Beifen

    2015-01-01

    The complement system, an important part of innate immunity, plays a critical role in pathogen clearance. Unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic virus including influenza A viruses H5N1, H7N9, and severe acute respiratory syndrome (SARS) coronavirus. In highly pathogenic virus-induced acute lung diseases, high levels of chemotactic and anaphylatoxic C5a were produced as a result of excessive complement activaiton. Overproduced C5a displays powerful biological activities in activation of phagocytic cells, generation of oxidants, and inflammatory sequelae named “cytokine storm”, and so on. Blockade of C5a signaling have been implicated in the treatment of ALI induced by highly pathogenic virus. Herein, we review the literature that links C5a and ALI, and review our understanding of the mechanisms by which C5a affects ALI during highly pathogenic viral infection. In particular, we discuss the potential of the blockade of C5a signaling to treat ALI induced by highly pathogenic viruses. PMID:26060601

  8. Protective effects of dexamethasone on early acute lung injury induced by oleic acid in rats

    PubMed Central

    Huang, Bin; Wang, Dao-Xin; Deng, Wang

    2014-01-01

    Objective: Whether alveolar edema could be cleared by alveolar epithelial is a key to the treatment and prognosis of ALI (acute lung injury). In this study, oleic acid(OA)-induced ALI model was established, the expression of α1 Na+/K+-ATPase (NKA) and β1 Na+/K+-ATPase were performed in vivo to investigate the mechanism of alveolar fluid clearance (AFC) in ALI and the effect of early low doses of dexamethasone on alveolar fluid clearance. Methods: In this study, Male rats were challenged by OA with or without dexamethasone (1 mg/kg, iv) post-treatment. Lung histopathology, blood gas, pulmonary vascular permeability, BALF IL-6, MPO and NKA activity of lung were examined. α1NKA and β1NKA mRNA and protein expression were detected. Results: The results indicated that compared with sham operated group, NKA activity, mRNA and protein expression of α1NKA and β1NKA were decreased in OA treated group, while wet/dry ratio, lung index, IL-6, and MPO activity were increased significantly. Pulmonary edema was obviously seen under light microscope. Those indexes were improved in dexamethasone treated group compared to OA treated group. Conclusion: The expression of NKA to decline for the lung injury is one important mechanism of pulmonary edema. Early low dose of dexamethasone treatment could suppress the expression of inflammatory mediators, improved lung epithelial-endothelial barrier permeability, increased the expressions of α1 NKA and β1 NKA mRNA, α1 NKA and β1 NKA protein level, stimulated NKA activity and decreased pulmonary edema. In conclusion, these observations suggest that early low dose of dexamethasone treatment has a protective effect on OA induced ALI. PMID:25663967

  9. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment.

    PubMed

    Garibaldi, Brian T; D'Alessio, Franco R; Mock, Jason R; Files, D Clark; Chau, Eric; Eto, Yoshiki; Drummond, M Bradley; Aggarwal, Neil R; Sidhaye, Venkataramana; King, Landon S

    2013-01-01

    Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1(-/-) mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1(-/-) mice received CD4(+)CD25(+) (Tregs) or CD4(+)CD25(-) Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1(-/-) mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1(-/-) mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1(-/-) mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI. PMID:23002097

  10. Pharmacologic Resuscitation Decreases Circulating CINC-1 Levels and Attenuates hemorrhage-Induced Acute Lung Injury

    PubMed Central

    Fukudome, Eugene Y.; Li, Yongqing; Kochanek, Ashley R.; Lu, Jennifer; Smith, Eleanor J.; Liu, Baoling; Kim, Kyuseok; Velmahos, George C.; deMoya, Marc A.; Alam, Hasan B.

    2016-01-01

    Background Acute lung injury (ALI) is a complication of hemorrhagic shock (HS). Histone deacetylase inhibitors (HDACI) such as valproic acid (VPA) can improve survival following HS, however, their effects on late organ injury are unknown. Here, we have investigated the effects of HS and VPA treatment on ALI as well as circulating cytokines that may serve as biomarkers for the development of organ injury. Materials and Methods Anesthetized Wistar-Kyoto rats (250-300g) underwent 40% blood volume hemorrhage over 10 minutes followed by 30 minutes of un-resuscitated shock and were treated with 1) VPA 300mg/kg or 2) vehicle control. Blood samples were obtained at baseline, following shock, and prior to sacrifice (1h, 4h, and 20h; n=3-4/timepoint/group). Serum samples were screened for possible biomarkers using a multiplex electrochemiluminescence detection assay, and results were confirmed using ELISA. Additionally, lung tissue lysate was examined for chemokine and myeloperoxidase (MPO) levels as a marker for neutrophil infiltration and ALI. Additionally, lung CINC-1 (a chemokine belonging to the IL-8 family that promotes neutrophil chemotaxis) mRNA levels were measured by real-time PCR. Results Serum screening revealed that hemorrhage rapidly altered levels of circulating CINC-1. ELISA confirmed that CINC-1 protein was significantly elevated in the serum as early as 4h, and in the lung at 20h following hemorrhage, without any significant changes in the CINC-1 mRNA expression. Lung MPO levels were also elevated 4h and 20h after hemorrhage. VPA treatment attenuated these changes Conclusions Hemorrhage resulted in development of ALI, which was prevented with VPA treatment. Circulating CINC-1 levels rose rapidly after hemorrhage, and serum CINC-1 levels correlated with lung CINC-1 and MPO levels. This suggests that circulating CINC-1 could be used as an early marker for the subsequent development of organ inflammation and injury. PMID:22657731

  11. Thromboxane A2 exacerbates acute lung injury via promoting edema formation.

    PubMed

    Kobayashi, Koji; Horikami, Daiki; Omori, Keisuke; Nakamura, Tatsuro; Yamazaki, Arisa; Maeda, Shingo; Murata, Takahisa

    2016-01-01

    Thromboxane A2 (TXA2) is produced in the lungs of patients suffering from acute lung injury (ALI). We assessed its contribution in disease progression using three different ALI mouse models. The administration of hydrochloric acid (HCl) or oleic acid (OA)+ lipopolysaccharide (LPS) caused tissue edema and neutrophil infiltration with TXA2 production in the lungs of the experimental mice. The administration of LPS induced only neutrophil accumulation without TXA2 production. Pretreatment with T prostanoid receptor (TP) antagonist attenuated the tissue edema but not neutrophil infiltration in these models. Intravital imaging and immunostaining demonstrated that administration of TP agonist caused vascular hyper-permeability by disrupting the endothelial barrier formation in the mouse ear. In vitro experiments showed that TP-stimulation disrupted the endothelial adherens junction, and it was inhibited by Ca(2+) channel blockade or Rho kinase inhibition. Thus endogenous TXA2 exacerbates ALI, and its blockade attenuates it by modulating the extent of lung edema. This can be explained by the endothelial hyper-permeability caused by the activation of TXA2-TP axis, via Ca(2+)- and Rho kinase-dependent signaling. PMID:27562142

  12. Thromboxane A2 exacerbates acute lung injury via promoting edema formation

    PubMed Central

    Kobayashi, Koji; Horikami, Daiki; Omori, Keisuke; Nakamura, Tatsuro; Yamazaki, Arisa; Maeda, Shingo; Murata, Takahisa

    2016-01-01

    Thromboxane A2 (TXA2) is produced in the lungs of patients suffering from acute lung injury (ALI). We assessed its contribution in disease progression using three different ALI mouse models. The administration of hydrochloric acid (HCl) or oleic acid (OA)+ lipopolysaccharide (LPS) caused tissue edema and neutrophil infiltration with TXA2 production in the lungs of the experimental mice. The administration of LPS induced only neutrophil accumulation without TXA2 production. Pretreatment with T prostanoid receptor (TP) antagonist attenuated the tissue edema but not neutrophil infiltration in these models. Intravital imaging and immunostaining demonstrated that administration of TP agonist caused vascular hyper-permeability by disrupting the endothelial barrier formation in the mouse ear. In vitro experiments showed that TP-stimulation disrupted the endothelial adherens junction, and it was inhibited by Ca2+ channel blockade or Rho kinase inhibition. Thus endogenous TXA2 exacerbates ALI, and its blockade attenuates it by modulating the extent of lung edema. This can be explained by the endothelial hyper-permeability caused by the activation of TXA2-TP axis, via Ca2+- and Rho kinase-dependent signaling. PMID:27562142

  13. Lung Neutrophilia in Myeloperoxidase Deficient Mice during the Course of Acute Pulmonary Inflammation.

    PubMed

    Kremserova, Silvie; Perecko, Tomas; Soucek, Karel; Klinke, Anna; Baldus, Stephan; Eiserich, Jason P; Kubala, Lukas

    2016-01-01

    Systemic inflammation accompanying diseases such as sepsis affects primarily lungs and induces their failure. This remains the most common cause of sepsis induced mortality. While neutrophils play a key role in pulmonary failure, the mechanisms remain incompletely characterized. We report that myeloperoxidase (MPO), abundant enzyme in neutrophil granules, modulates the course of acute pulmonary inflammatory responses induced by intranasal application of lipopolysaccharide. MPO deficient mice had significantly increased numbers of airway infiltrated neutrophils compared to wild-type mice during the whole course of lung inflammation. This was accompanied by higher levels of RANTES in bronchoalveolar lavage fluid from the MPO deficient mice. Other markers of lung injury and inflammation, which contribute to recruitment of neutrophils into the inflamed lungs, including total protein and other selected proinflammatory cytokines did not significantly differ in bronchoalveolar lavage fluid from the wild-type and the MPO deficient mice. Interestingly, MPO deficient neutrophils revealed a decreased rate of cell death characterized by phosphatidylserine surface expression. Collectively, the importance of MPO in regulation of pulmonary inflammation, independent of its putative microbicidal functions, can be potentially linked to MPO ability to modulate the life span of neutrophils and to affect accumulation of chemotactic factors at the inflammatory site. PMID:26998194

  14. Activated protein C attenuates acute lung injury and apoptosis in a hyperoxic animal model.

    PubMed

    Husari, Ahmad W; Khayat, Aline; Awdeh, Haitham; Hatoum, Hadi; Nasser, Michel; Mroueh, Salman M; Zaatari, Ghazi; El-Sabban, Marwan; Dbaibo, Ghassan S

    2010-05-01

    Evidence suggests that activated protein C (APC) attenuates acute lung injury (ALI) through antithrombotic and anti-inflammatory mechanisms. The aim of this study was to determine the effects of APC on ALI in adult rats exposed to hyperoxic environment. Rats were divided into control, hyperoxia, hyperoxia + APC, and APC. Hyperoxia and hyperoxia + APC were exposed to 1, 3, and 5 days of hyperoxia. Hyperoxia + APC and APC were injected with APC (5 mg/kg, i.p.) every 12 h. Control and hyperoxia received isotonic sodium chloride solution injection. Measurement of wet to dry ratio and albumin leak demonstrated significant improvement in hyperoxia + APC when compared with hyperoxia. Apoptosis, as measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, was significantly reduced in hyperoxia + APC when compared with hyperoxia. Histological evaluation of lung sections showed significant reduction in inflammation, edema, and in the number of marginating neutrophils in hyperoxia + APC as compared with hyperoxia. Transcriptional expression of lung inflammatory mediators demonstrated a time-dependent surge in the levels TNF-alpha, IL-1beta, and IL-6 in response to hyperoxia that was attenuated with APC administration in the presence of hyperoxia. In this rat model, APC attenuates lung injury and the expression of inflammatory mediators in ALI secondary to hyperoxia. PMID:19851127

  15. Pathophysiological Approaches of Acute Respiratory Distress syndrome: Novel Bases for Study of Lung Injury

    PubMed Central

    Castillo, R.L; Carrasco Loza, R; Romero-Dapueto, C

    2015-01-01

    Experimental approaches have been implemented to research the lung damage related-mechanism. These models show in animals pathophysiological events for acute respiratory distress syndrome (ARDS), such as neutrophil activation, reactive oxygen species burst, pulmonary vascular hypertension, exudative edema, and other events associated with organ dysfunction. Moreover, these approaches have not reproduced the clinical features of lung damage. Lung inflammation is a relevant event in the develop of ARDS as component of the host immune response to various stimuli, such as cytokines, antigens and endotoxins. In patients surviving at the local inflammatory states, transition from injury to resolution is an active mechanism regulated by the immuno-inflammatory signaling pathways. Indeed, inflammatory process is regulated by the dynamics of cell populations that migrate to the lung, such as neutrophils and on the other hand, the role of the modulation of transcription factors and reactive oxygen species (ROS) sources, such as nuclear factor kappaB and NADPH oxidase. These experimental animal models reproduce key components of the injury and resolution phases of human ALI/ARDS and provide a methodology to explore mechanisms and potential new therapies. PMID:26312099

  16. Piperine Ameliorates Lipopolysaccharide-Induced Acute Lung Injury via Modulating NF-κB Signaling Pathways.

    PubMed

    Lu, Ying; Liu, Jingyao; Li, Hongyan; Gu, Lina

    2016-02-01

    Piperine, one of the active components of black pepper, has been reported to have antioxidant and anti-inflammatory activities. However, the effects of piperine on lipolysaccharide (LPS)-induced acute lung injury (ALI) have not been reported. Thus, the protective effects of piperine against LPS-induced ALI were investigated in this study. LPS-induced lung injury was assessed by histological study, myeloperoxidase (MPO) activity, and inflammatory cytokine production. Our results demonstrated that piperine attenuated LPS-induced MPO activity, lung edema, and inflammatory cytokines TNF-α, IL-6, and IL-1β production. Histological studies showed that piperine obviously attenuated LPS-induced lung injury. In addition, piperine significantly inhibited LPS-induced NF-κB activation. In conclusion, our results demonstrated that piperine had a protective effect on LPS-induced ALI. The anti-inflammatory mechanism of piperine is through inhibition of NF-κB activation. Piperine may be a potential therapeutic agent for ALI. PMID:26410851

  17. Impact of mechanical ventilation on the pathophysiology of progressive acute lung injury.

    PubMed

    Nieman, Gary F; Gatto, Louis A; Habashi, Nader M

    2015-12-01

    The earliest description of what is now known as the acute respiratory distress syndrome (ARDS) was a highly lethal double pneumonia. Ashbaugh and colleagues (Ashbaugh DG, Bigelow DB, Petty TL, Levine BE Lancet 2: 319-323, 1967) correctly identified the disease as ARDS in 1967. Their initial study showing the positive effect of mechanical ventilation with positive end-expiratory pressure (PEEP) on ARDS mortality was dampened when it was discovered that improperly used mechanical ventilation can cause a secondary ventilator-induced lung injury (VILI), thereby greatly exacerbating ARDS mortality. This Synthesis Report will review the pathophysiology of ARDS and VILI from a mechanical stress-strain perspective. Although inflammation is also an important component of VILI pathology, it is secondary to the mechanical damage caused by excessive strain. The mechanical breath will be deconstructed to show that multiple parameters that comprise the breath-airway pressure, flows, volumes, and the duration during which they are applied to each breath-are critical to lung injury and protection. Specifically, the mechanisms by which a properly set mechanical breath can reduce the development of excessive fluid flux and pulmonary edema, which are a hallmark of ARDS pathology, are reviewed. Using our knowledge of how multiple parameters in the mechanical breath affect lung physiology, the optimal combination of pressures, volumes, flows, and durations that should offer maximum lung protection are postulated. PMID:26472873

  18. Lung Neutrophilia in Myeloperoxidase Deficient Mice during the Course of Acute Pulmonary Inflammation

    PubMed Central

    Kremserova, Silvie; Perecko, Tomas; Soucek, Karel; Klinke, Anna; Baldus, Stephan; Eiserich, Jason P.; Kubala, Lukas

    2016-01-01

    Systemic inflammation accompanying diseases such as sepsis affects primarily lungs and induces their failure. This remains the most common cause of sepsis induced mortality. While neutrophils play a key role in pulmonary failure, the mechanisms remain incompletely characterized. We report that myeloperoxidase (MPO), abundant enzyme in neutrophil granules, modulates the course of acute pulmonary inflammatory responses induced by intranasal application of lipopolysaccharide. MPO deficient mice had significantly increased numbers of airway infiltrated neutrophils compared to wild-type mice during the whole course of lung inflammation. This was accompanied by higher levels of RANTES in bronchoalveolar lavage fluid from the MPO deficient mice. Other markers of lung injury and inflammation, which contribute to recruitment of neutrophils into the inflamed lungs, including total protein and other selected proinflammatory cytokines did not significantly differ in bronchoalveolar lavage fluid from the wild-type and the MPO deficient mice. Interestingly, MPO deficient neutrophils revealed a decreased rate of cell death characterized by phosphatidylserine surface expression. Collectively, the importance of MPO in regulation of pulmonary inflammation, independent of its putative microbicidal functions, can be potentially linked to MPO ability to modulate the life span of neutrophils and to affect accumulation of chemotactic factors at the inflammatory site. PMID:26998194

  19. Acute effects of volcanic ash from Mount Saint Helens on lung function in children.

    PubMed

    Buist, A S; Johnson, L R; Vollmer, W M; Sexton, G J; Kanarek, P H

    1983-06-01

    To evaluate the acute effects of volcanic ash from Mt. St. Helens on the lung function of children, we studied 101 children 8 to 13 yr of age who were attending a 2-wk summer camp for children with diabetes mellitus in an area where about 1.2 cm of ash had fallen after the June 12, 1980, eruption. The outcome variables used were forced vital capacity, forced expiratory volume in one second, their ratio and mean transit time. Total and respirable dust levels were measured using personal sampling pumps. The children were tested on arrival and twice (early morning [A.M.] and late afternoon [P.M.]) every second or third day during the session. A within-day effect was measured by the P.M./A.M. ratio for the lung function variables; a between-day effect was measured by the change in the P.M. measurements over the 2 wk of camp. We found no strong evidence of either a within-day or a between-day effect on lung function, even in a subgroup of children who had preexisting lung disease or symptoms, despite daytime dust/ash levels that usually exceeded the Environmental Protection Agency's significant harm level for particulate matter. PMID:6859654

  20. Effects of methylene blue in acute lung injury induced by oleic acid in rats

    PubMed Central

    Cassiano Silveira, Ana Paula; Vento, Daniella Alves; Albuquerque, Agnes Afrodite Sumarelli; Celotto, Andrea Carla; Tefé-Silva, Cristiane; Ramos, Simone Gusmão; Rubens de Nadai, Tales; Rodrigues, Alfredo José; Poli-Neto, Omero Benedicto

    2016-01-01

    Background In acute lung injury (ALI), rupture of the alveolar-capillary barrier determines the protein-rich fluid influx into alveolar spaces. Previous studies have reported that methylene blue (MB) attenuates such injuries. This investigation was carried out to study the MB effects in pulmonary capillary permeability. Methods Wistar rats were divided into five groups: (I) Sham: saline bolus; (II) MB, MB infusion for 2 h; (III) oleic acid (OA), OA bolus; (IV) MB/OA, MB infusion for 2 h, and at 5 min after from the beginning, concurrently with an OA bolus; and (V) OA/MB, OA bolus, and after 2 h, MB infusion for 2 h. After 4 h, blood, bronchoalveolar lavage (BAL), and lung tissue were collected from all groups for analysis of plasma and tissue nitric oxide, calculation of the wet weight to dry weight ratio (WW/DW), and histological examination of lung tissue. Statistical analysis was performed using nonparametric test. Results Although favourable trends have been observed for permeability improvement parameters (WW/WD and protein), the results were not statistically significant. However, histological analysis of lung tissue showed reduced lesion areas in both pre- and post-treatment groups. Conclusions The data collected using this experimental model was favourable only through macroscopic and histological analysis. These observations are valid for both MB infusions before or after induction of ALI. PMID:26855944

  1. Anorexia, serum zinc, and immunologic response in small cell lung cancer patients receiving chemotherapy and prophylactic cranial radiotherapy.

    PubMed

    Lindsey, A M; Piper, B F

    1986-01-01

    Anorexia is a major clinical problem for patients with certain types of cancer. The specific mechanisms that result in this spontaneous decline in food intake remain unknown. In noncancer populations, zinc has been shown to play a role in maintaining normal appetite, taste acuity, and immunocompetence. One purpose of this prospective, longitudinal study of cachexia in ten males with small cell lung carcinoma was to determine if anorexia (caloric intake), perceived taste changes, zinc intake, and impaired cellular immunity were associated with serum zinc concentrations. The average daily caloric intake declined 490 kcal from time of diagnosis to seven months after diagnosis (mean caloric intake = 72% of RDA). Daily zinc intake ranged from 6.5 to 25.4 mg over the seven months. During this period, the mean serum zinc concentrations, although low (71 micrograms/dl), remained within the normal range. The average weight declined from 81.7 to 74.1 kg. There was no identifiable pattern of perceived taste changes; most of the perceived changes were recorded during the period coinciding with prophylactic cranial radiation. At the initial testing, four of nine subjects were anergic to a battery of skin test antigens (mumps, candida, tuberculin purified protein derivative). The only subject who remained responsive to two antigens throughout the study remained alive at 12 months. Caloric intake was inadequate to maintain weight. While zinc intake was low, low normal serum zinc concentrations were maintained; thus in this sample, serum zinc does not appear to be the anorexigenic factor. PMID:3022247

  2. Protective effect of carvacrol on acute lung injury induced by lipopolysaccharide in mice.

    PubMed

    Feng, Xiaosheng; Jia, Aiqing

    2014-08-01

    Carvacrol, the major component of Plectranthus amboinicus, has been known to exhibit anti-inflammatory activities. The aim of this study was to investigate the effects of carvacrol on lipopolysaccharide (LPS)-induced endotoxemia and acute lung injury (ALI) in mice. Mice were injected intraperitoneally (i.p.) with LPS and the mortality of mice for 7 days were observed twice a day. Meanwhile, the protective effect of carvacrol (20, 40 or 80 mg/kg) on LPS-induced endotoxemia were detected. Using an experimental model of LPS-induced ALI, we examined the effect of carvacrol in resolving lung injury. The results showed that carvacrol could improve survival during lethal endotoxemia and attenuate LPS-induced ALI in mice. The anti-inflammatory mechanisms of carvacrol may be due to its ability to inhibit NF-κB and MAPKs signaling pathways, thereby inhibiting inflammatory cytokines TNF-α, IL-6 and IL-1β production. PMID:24577726

  3. State of the art management of transfusion-related acute lung injury (TRALI).

    PubMed

    Goldberg, Andrew D; Kor, Daryl J

    2012-01-01

    Transfusion-Related Acute Lung Injury (TRALI) is the leading cause of transfusion-related mortality in most developed countries. Despite this fact, well-designed investigations on specific management strategies for TRALI are lacking. Indeed, current recommendations are primarily based on data extrapolated from trials of the histo-pathologically similar Acute Lung Injury and Acute Respiratory Distress Syndromes. The cornerstone of TRALI management is supportive care with oxygen supplementation and ventilatory assistance when needed. When mechanical ventilation is required, attenuating additional ventilator-induced lung injury through the avoidance of high tidal volumes and elevated airway pressures, with additional measures such as positive end-expiratory pressure to prevent low-volume shear stress injury, are recommended. The literature is not currently sufficient to support either corticosteroids or statins as effective therapies in TRALI. Conservative fluid practices are desirable, provided care is taken to avoid hypotension. Preventative strategies have shown the most promise in mitigating this transfusion-related pulmonary complication. Specifically, conservative transfusion practices and deferral of high-plasma component donors who have, or at high risk of having, anti-human leukocyte antigen and/or anti-human neutrophil antigen antibodies have meaningfully impacted the incidence of TRALI. Future considerations for patients who are at increased risk for developing TRALI may include therapies such as anti-platelet agents and alternatives to traditional blood components such as prothrombin complex concentrates (PCC). However, these potential TRALI prevention strategies are insufficiently studied, have unclear risk/benefit profiles and cannot be currently recommended. PMID:22621274

  4. A new experimental model of acid- and endotoxin-induced acute lung injury in rats.

    PubMed

    Puig, F; Herrero, R; Guillamat-Prats, R; Gómez, M N; Tijero, J; Chimenti, L; Stelmakh, O; Blanch, L; Serrano-Mollar, A; Matthay, M A; Artigas, A

    2016-08-01

    The majority of the animal models of acute lung injury (ALI) are focused on the acute phase. This limits the studies of the mechanisms involved in later phases and the effects of long-term treatments. Thus the goal of this study was to develop an experimental ALI model of aspiration pneumonia, in which diffuse alveolar damage continues for 72 h. Rats were intratracheally instilled with one dose of HCl (0.1 mol/l) followed by another instillation of one dose of LPS (0, 10, 20, 30, or 40 μg/g body weight) 2 h later, which models aspiration of gastric contents that progresses to secondary lung injury from bacteria or bacterial products. The rats were euthanized at 24, 48, and 72 h after the last instillation. The results showed that HCl and LPS at all doses caused activation of inflammatory responses, increased protein permeability and apoptosis, and induced mild hypoxemia in rat lungs at 24 h postinstillation. However, this lung damage was present at 72 h only in rats receiving HCl and LPS at the doses of 30 and 40 μg/g body wt. Mortality (∼50%) occurred in the first 48 h and only in the rats treated with HCl and LPS at the highest dose (40 μg/g body wt). In conclusion, intratracheal instillation of HCl followed by LPS at the dose of 30 μg/g body wt results in severe diffuse alveolar damage that continues at least 72 h. This rat model of aspiration pneumonia-induced ALI will be useful for testing long-term effects of new therapeutic strategies in ALI. PMID:27317688

  5. Synthetic Amphipathic Helical Peptides Targeting CD36 Attenuate Lipopolysaccharide-Induced Inflammation and Acute Lung Injury.

    PubMed

    Bocharov, Alexander V; Wu, Tinghuai; Baranova, Irina N; Birukova, Anna A; Sviridov, Denis; Vishnyakova, Tatyana G; Remaley, Alan T; Eggerman, Thomas L; Patterson, Amy P; Birukov, Konstantin G

    2016-07-15

    Synthetic amphipathic helical peptides (SAHPs) designed as apolipoprotein A-I mimetics are known to bind to class B scavenger receptors (SR-Bs), SR-BI, SR-BII, and CD36, receptors that mediate lipid transport and facilitate pathogen recognition. In this study, we evaluated SAHPs, selected for targeting human CD36, by their ability to attenuate LPS-induced inflammation, endothelial barrier dysfunction, and acute lung injury (ALI). L37pA, which targets CD36 and SR-BI equally, inhibited LPS-induced IL-8 secretion and barrier dysfunction in cultured endothelial cells while reducing lung neutrophil infiltration by 40% in a mouse model of LPS-induced ALI. A panel of 20 SAHPs was tested in HEK293 cell lines stably transfected with various SR-Bs to identify SAHPs with preferential selectivity toward CD36. Among several SAHPs targeting both SR-BI/BII and CD36 receptors, ELK-B acted predominantly through CD36. Compared with L37pA, 5A, and ELK SAHPs, ELK-B was most effective in reducing the pulmonary barrier dysfunction, neutrophil migration into the lung, and lung inflammation induced by LPS. We conclude that SAHPs with relative selectivity toward CD36 are more potent at inhibiting acute pulmonary inflammation and dysfunction. These data indicate that therapeutic strategies using SAHPs targeting CD36, but not necessarily mimicking all apolipoprotein A-I functions, may be considered a possible new treatment approach for inflammation-induced ALI and pulmonary edema. PMID:27316682

  6. Cytoskeletal mechanisms regulating vascular endothelial barrier function in response to acute lung injury.

    PubMed

    Kása, Anita; Csortos, Csilla; Verin, Alexander D

    2015-01-01

    Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. In acute lung injury (ALI) the EC barrier is weakened leading to increased vascular permeability. It is widely accepted that EC barrier integrity is critically dependent upon intact cytoskeletal structure and cell junctions. Edemagenic agonists, like thrombin or endotoxin lipopolysaccharide (LPS), induced cytoskeletal rearrangement, and EC contractile responses leading to disruption of intercellular contacts and EC permeability increase. The highly clinically-relevant cytoskeletal mechanisms of EC barrier dysfunction are currently under intense investigation and will be described and discussed in the current review. PMID:25838980

  7. Cytoskeletal mechanisms regulating vascular endothelial barrier function in response to acute lung injury

    PubMed Central

    Kása, Anita; Csortos, Csilla; Verin, Alexander D

    2014-01-01

    Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. In acute lung injury (ALI) the EC barrier is weakened leading to increased vascular permeability. It is widely accepted that EC barrier integrity is critically dependent upon intact cytoskeletal structure and cell junctions. Edemagenic agonists, like thrombin or endotoxin lipopolysaccharide (LPS), induced cytoskeletal rearrangement, and EC contractile responses leading to disruption of intercellular contacts and EC permeability increase. The highly clinically-relevant cytoskeletal mechanisms of EC barrier dysfunction are currently under intense investigation and will be described and discussed in the current review. PMID:25838980

  8. Effects of basic drugs on prognosis of acute lung injury in mice.

    PubMed

    Jia, Liming; Ren, Junming; Zhang, Weiwei; Qi, Yuehong; Zheng, Lina; Guo, Yongqing

    2015-01-01

    The aim of this study was to investigate the effects of basic drugs that alkalizes blood, on prognosis of acute lung injury in mice. Mice were randomized into three groups: Group normal saline, Group THAM, injected with 3.64% tri-(hydroxymethyl) methylamine (THAM), and Group NaHCO3, injected with 5% NaHCO3 (n=26, each group). The acute lung injury model was established by intraperitoneal injection of lipopolysaccharide (LPS; 50 mg/kg), followed by infusion of varying concentrations of the above solution into tail vein at the rate of 0.5 ml/h (controlled by micro pump) for over 2 h. Thirty minutes later, 6 mice from each group were randomly selected for blood gas analysis; then, the mice were killed and their lung tissues were sampled for detection of relative indicators, and the remaining mice were observed for signs of mortality for 72 h. Arterial pH, bicarbonate (HCO3 (-)), and BE and mortality of group THAM and NaHCO3 increased significantly compared to the corresponding parameters of the group normal saline (P<0.05); compared to the group normal saline, group NaHCO3 had increased blood [Na(+)] and decreased [K(+)] and [Ca(2+)] (P<0.05). Blood [Na(+)] of group THAM decreased while the lactic acid concentration increased (P<0.05) compared to the corresponding values of the group normal saline. Malondialdehyde (MDA) and myeloperoxidase (MPO) activity and wet-to-dry lung weight ratio (W/D) of group THAM and NaHCO3 increased significantly relative to group normal saline (P<0.05). Compared with the biopsy results of (A), pathological biopsy of (B) and (C) clearly revealed alveolar wall thickening, edema of alveolar epithelial cells, and infiltration of large neutrophils. Alkalizing blood could neither inhibit inflammatory reactions in LPS mouse model nor reduce the mortality rate of mice with acute lung injury, while excessive alkalization of blood could increase mice mortality. PMID:26770536

  9. Curcumin protects against sepsis-induced acute lung injury in rats.

    PubMed

    Xiao, Xuefei; Yang, Mingshi; Sun, Dao; Sun, Shenghua

    2012-07-01

    The present study aimed to investigate the effect of curcumin on sepsis-induced acute lung injury (ALI) in rats, and explore its possible mechanisms. Male Sprague-Dawley rats were randomly divided into the following five experimental groups (n = 20 per group): animals undergoing a sham cecal ligature puncture (CLP) (sham group); animals undergoing CLP (control group); or animals undergoing CLP and treated with vehicle (vehicle group), curcumin at 50 mg/kg (low-dose curcumin [L-Cur] group), or curcumin at 200 mg/kg (high-dose curcumin [H-Cur] group).At 6, 12, 24 h after CLP, blood, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level, and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathologic changes in lungs. Myeloperoxidase (MPO) activity, malondialdehyde (MDA) content, as well as superoxidase dismutase (SOD) activity were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interluekin-8 (IL-8), and macrophage migration inhibitory factor (MIF) were determined in the BALF. Survival rates were recorded at 72 h in the five groups in another experiment. Treatment with curcumin significantly attenuated the CLP-induced pulmonary edema and inflammation, as it significantly decreased lung W/D ratio, protein concentration, and the accumulation of the inflammatory cells in the BALF, as well as pulmonary MPO activity. This was supported by the histopathologic examination, which revealed marked attenuation of CLP-induced ALI in curcumin treated rats. In addition, curcumin significantly increased SOD activity with significant decrease in MDA content in the lung. Also, curcumin caused down-regulation of the inflammatory cytokines TNF-α, IL-8, and MIF levels in the lung. Importantly, curcumin improved the survival rate of rats by 40%-50% with CLP-induced ALI. Taken together, these results

  10. Abdominal Muscle Activity during Mechanical Ventilation Increases Lung Injury in Severe Acute Respiratory Distress Syndrome

    PubMed Central

    Zhang, Xianming; Wu, Weiliang; Zhu, Yongcheng; Jiang, Ying; Du, Juan; Chen, Rongchang

    2016-01-01

    Objective It has proved that muscle paralysis was more protective for injured lung in severe acute respiratory distress syndrome (ARDS), but the precise mechanism is not clear. The purpose of this study was to test the hypothesis that abdominal muscle activity during mechanically ventilation increases lung injury in severe ARDS. Methods Eighteen male Beagles were studied under mechanical ventilation with anesthesia. Severe ARDS was induced by repetitive oleic acid infusion. After lung injury, Beagles were randomly assigned into spontaneous breathing group (BIPAPSB) and abdominal muscle paralysis group (BIPAPAP). All groups were ventilated with BIPAP model for 8h, and the high pressure titrated to reached a tidal volume of 6ml/kg, the low pressure was set at 10 cmH2O, with I:E ratio 1:1, and respiratory rate adjusted to a PaCO2 of 35–60 mmHg. Six Beagles without ventilator support comprised the control group. Respiratory variables, end-expiratory volume (EELV) and gas exchange were assessed during mechanical ventilation. The levels of Interleukin (IL)-6, IL-8 in lung tissue and plasma were measured by qRT-PCR and ELISA respectively. Lung injury scores were determined at end of the experiment. Results For the comparable ventilator setting, as compared with BIPAPSB group, the BIPAPAP group presented higher EELV (427±47 vs. 366±38 ml) and oxygenation index (293±36 vs. 226±31 mmHg), lower levels of IL-6(216.6±48.0 vs. 297.5±71.2 pg/ml) and IL-8(246.8±78.2 vs. 357.5±69.3 pg/ml) in plasma, and lower express levels of IL-6 mRNA (15.0±3.8 vs. 21.2±3.7) and IL-8 mRNA (18.9±6.8 vs. 29.5±7.9) in lung tissues. In addition, less lung histopathology injury were revealed in the BIPAPAP group (22.5±2.0 vs. 25.2±2.1). Conclusion Abdominal muscle activity during mechanically ventilation is one of the injurious factors in severe ARDS, so abdominal muscle paralysis might be an effective strategy to minimize ventilator-induce lung injury. PMID:26745868

  11. Development of a Multicomponent Prediction Model for Acute Esophagitis in Lung Cancer Patients Receiving Chemoradiotherapy

    SciTech Connect

    De Ruyck, Kim; Sabbe, Nick; Oberije, Cary; Vandecasteele, Katrien; Thas, Olivier; De Ruysscher, Dirk; Lambin, Phillipe; Van Meerbeeck, Jan; De Neve, Wilfried; Thierens, Hubert

    2011-10-01

    Purpose: To construct a model for the prediction of acute esophagitis in lung cancer patients receiving chemoradiotherapy by combining clinical data, treatment parameters, and genotyping profile. Patients and Methods: Data were available for 273 lung cancer patients treated with curative chemoradiotherapy. Clinical data included gender, age, World Health Organization performance score, nicotine use, diabetes, chronic disease, tumor type, tumor stage, lymph node stage, tumor location, and medical center. Treatment parameters included chemotherapy, surgery, radiotherapy technique, tumor dose, mean fractionation size, mean and maximal esophageal dose, and overall treatment time. A total of 332 genetic polymorphisms were considered in 112 candidate genes. The predicting model was achieved by lasso logistic regression for predictor selection, followed by classic logistic regression for unbiased estimation of the coefficients. Performance of the model was expressed as the area under the curve of the receiver operating characteristic and as the false-negative rate in the optimal point on the receiver operating characteristic curve. Results: A total of 110 patients (40%) developed acute esophagitis Grade {>=}2 (Common Terminology Criteria for Adverse Events v3.0). The final model contained chemotherapy treatment, lymph node stage, mean esophageal dose, gender, overall treatment time, radiotherapy technique, rs2302535 (EGFR), rs16930129 (ENG), rs1131877 (TRAF3), and rs2230528 (ITGB2). The area under the curve was 0.87, and the false-negative rate was 16%. Conclusion: Prediction of acute esophagitis can be improved by combining clinical, treatment, and genetic factors. A multicomponent prediction model for acute esophagitis with a sensitivity of 84% was constructed with two clinical parameters, four treatment parameters, and four genetic polymorphisms.

  12. Dual hit lipopolysaccharide & oleic acid combination induced rat model of acute lung injury/acute respiratory distress syndrome

    PubMed Central

    Hagawane, T.N.; Gaikwad, R.V.; Kshirsagar, N.A.

    2016-01-01

    Background & objectives: Despite advances in therapy and overall medical care, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) management remains a problem. Hence the objective of this study was to develop a rat model that mimics human ALI/ARDS. Methods: Four groups of Wistar rats, 48 per group were treated with (i) intratracheal (IT) lipopolysaccharide (LPS) (5 mg/kg) dissolved in normal saline (NS), (ii) intravenous (iv) oleic acid (OA) (250 μl/kg) suspension in bovine serum albumin (BSA), (iii) dual hit: IT LPS (2 mg/kg) dissolved in NS and iv OA (100 μl/kg) and (iv) control group: IT NS and iv BSA. From each group at set periods of time various investigations like chest X-rays, respiratory rate (RR), tidal volume (TV), total cell count, differential cell count, total protein count and cytokine levels in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio and histopathological examination were done. Results: It was noted that the respiratory rate, and tumour necrosis factor-α (TNF-α) levels were significantly higher at 4 h in the dual hit group as compared to LPS, OA and control groups. Interleukin-6 (IL-6) levels were significantly higher in the dual hit group as compared to LPS at 8 and 24 h, OA at 8 h and control (at all time intervals) group. IL-1β levels were significantly higher in LPS and dual hit groups at all time intervals, but not in OA and control groups. The injury induced in dual hit group was earlier and more sustained as compared to LPS and OA alone. Interpretation & conclusions: The lung pathology and changes in respiration functions produced by the dual hit model were closer to the diagnostic criteria of ALI/ARDS in terms of clinical manifestations and pulmonary injury and the injury persisted longer as compared to LPS and OA single hit model. Therefore, the ARDS model produced by the dual hit method was closer to the diagnostic criteria of ARDS in terms of clinical manifestations and pulmonary injury. PMID

  13. Protective effects of thoracic epidural anesthesia on hypoxia-induced acute lung injury in rabbits

    PubMed Central

    WANG, LIJUN; CANG, JING; XUE, ZHANGGANG

    2016-01-01

    The mechanism underlying the effect of thoracic epidural anesthesia (TEA) on hypoxia-induced acute lung injury (ALI) is currently unknown. In the present study, a rabbit acute lung injury model was established to investigate the effects of TEA on inflammatory factors, pulmonary surfactant and ultrastructure. A total of 56 rabbits were randomly assigned to four groups (n=14 per group): Control group (Group C), hypoxia group (Group H), sevoflurane group (Group S) and combined sevoflurane-epidural anesthesia group (Group ES). The ALI model was considered to have been successfully induced when the ratio of arterial oxygen partial pressure to fractional inspired oxygen was <300. The correct placement of a catheter for TEA was confirmed using epidurography. ALI was maintained for 3 h. Arterial blood samples were collected from all groups during spontaneous breathing (T0) and at 3 h after ALI induction (T5) in order to evaluate the serum levels of interleukin (IL)-6, IL-8 and IL-10. Bronchoalveolar lavage fluid was harvested to determine the total phospholipid, saturated phosphatidylcholine and total protein levels. Furthermore, the dry/wet weight ratio and the mRNA expression levels of IL-6, IL-8 and IL-10 in the lung tissue were determined using ELISA. In addition, light and transmission electron microscopy and histological techniques were used to examine the morphology of alveolar type II cells in the rat lung tissue. The results indicate that changes of serum IL-6, IL-8 and IL-10 levels following ALI were consistent with the changes in the mRNA expression levels of IL-6, IL-8 and IL-10 in the lung tissue. TEA attenuated these changes and thus reduced the severity of the ALI. In addition, TEA improved the alveolar structure, reduced the number of polymorphonuclear cells and mitigated the damage of lamellar bodies. In summary, the results of the present study indicate that TEA reduces lung tissue damage by inhibiting systemic and local inflammation, decreasing the

  14. Regulatory cells induced by acute toxoplasmosis prevent the development of allergic lung inflammation.

    PubMed

    Fenoy, Ignacio M; Sanchez, Vanesa R; Soto, Ariadna S; Picchio, Mariano S; Maglioco, Andrea; Corigliano, Mariana G; Dran, Graciela I; Martin, Valentina; Goldman, Alejandra

    2015-05-01

    The increased prevalence of allergies in developed countries has been attributed to a reduction of some infections. Supporting epidemiological studies, we previously showed that both acute and chronic Toxoplasma gondii infection can diminish allergic airway inflammation in BALB/c mice. The mechanisms involved when sensitization occurs during acute phase would be related to the strong Th1 response induced by the parasite. Here, we further investigated the mechanisms involved in T. gondii allergy protection in mice sensitized during acute T. gondii infection. Adoptive transference assays and ex vivo co-cultures experiments showed that not only thoracic lymph node cells from infected and sensitized mice but also from non-sensitized infected animals diminished both allergic lung inflammation and the proliferation of effector T cells from allergic mice. This ability was found to be contact-independent and correlated with high levels of CD4(+)FoxP3(+) cells. IL-10 would not be involved in allergy suppression since IL-10-deficient mice behaved similar to wild type mice. Our results extend earlier work and show that, in addition to immune deviation, acute T. gondii infection can suppress allergic airway inflammation through immune suppression. PMID:25532793

  15. Aging has small effects on initial ischemic acute kidney injury development despite changing intrarenal immunologic micromilieu in mice.

    PubMed

    Jang, Hye Ryoun; Park, Ji Hyeon; Kwon, Ghee Young; Park, Jae Berm; Lee, Jung Eun; Kim, Dae Joong; Kim, Yoon-Goo; Kim, Sung Joo; Oh, Ha Young; Huh, Wooseong

    2016-02-15

    Inflammatory process mediated by innate and adaptive immune systems is a major pathogenic mechanism of renal ischemia-reperfusion injury (IRI). There are concerns that organ recipients may be at increased risk of developing IRI after receiving kidneys from elder donors. To reveal the effects of aging on the development of renal IRI, we compared the immunologic micromilieu of normal and postischemic kidneys from mice of three different ages (9 wk, 6 mo, and 12 mo). There was a higher number of total T cells, especially effector memory CD4/CD8 T cells, and regulatory T cells in the normal kidneys of old mice. On day 2 after IRI, the proportion of necrotic tubules and renal functional changes were comparable between groups although old mice had a higher proportion of damaged tubule compared with young mice. More T cells, but less B cells, trafficked into the postischemic kidneys of old mice. The infiltration of NK T cells was similar across the groups. Macrophages and neutrophils were comparable between groups in both normal kidneys and postischemic kidneys. The intrarenal expressions of TNF-α and VEGF were decreased in normal and postischemic kidneys of aged mice. These mixed effects of aging on lymphocytes and cytokines/chemokines were not different between the two groups of old mice. Our study demonstrates that aging alters the intrarenal micromilieu but has small effects on the development of initial renal injury after IRI. Further study investigating aging-dependent differences in the repair process of renal IRI may be required. PMID:26661651

  16. Characterization of a nose-only inhaled phosgene acute lung injury mouse model

    PubMed Central

    Plahovinsak, Jennifer L.; Perry, Mark R.; Knostman, Katherine A.; Segal, Robert; Babin, Michael C.

    2016-01-01

    Context Phosgene’s primary mode of action is as a pulmonary irritant characterized by its early latent phase where life-threatening, non-cardiogenic pulmonary edema is typically observed 6–24 h post-exposure. Objective To develop an inhaled phosgene acute lung injury (ALI) model in C57BL/6 mice that can be used to screen potential medical countermeasures. Methods A Cannon style nose-only inhalation exposure tower was used to expose mice to phosgene (8 ppm) or air (sham). An inhalation lethality study was conducted to determine the 8 ppm median lethal exposure (LCt50) at 24 and 48 h post-exposure. The model was then developed at 1.2 times the 24 h LCt50. At predetermined serial sacrifice time points, survivors were euthanized, body and lung weights collected, and lung tissues processed for histopathology. Additionally, post-exposure clinical observations were used to assess quality of life. Results and discussion The 24-hour LCt50 was 226ppm*min (8 ppm for 28.2 min) and the 48-hour LCt50 was 215ppm*min (8 ppm for 26.9 min). The phosgene exposed animals had a distinct progression of clinical signs, histopathological changes and increased lung/body weight ratios. Early indicators of a 1.2 times the 24-hour LCt50 phosgene exposure were significant changes in the lung-to-body weight ratios by 4 h post-exposure. The progression of clinical signs and histopathological changes were important endpoints for characterizing phosgene-induced ALI for future countermeasure studies. Conclusion An 8 ppm phosgene exposure for 34 min (1.2 × LCt50) is the minimum challenge recommended for evaluating therapeutic interventions. The predicted higher mortality in the phosgene-only controls will help demonstrate efficacy of candidate treatments and increase the probability that a change in survival rate is statistically significant PMID:26671199

  17. The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation.

    PubMed

    Grabiec, Aleksander M; Hussell, Tracy

    2016-07-01

    Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called 'efferocytosis'. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections. PMID:26957481

  18. Endothelial Nitric Oxide Synthase Deficient Mice Are Protected from Lipopolysaccharide Induced Acute Lung Injury

    PubMed Central

    Gross, Christine M.; Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh; Ham III, P. Benson; Meadows, Mary Louise; Cherian-Shaw, Mary; Kangath, Archana; Sridhar, Supriya; Lucas, Rudolf; Black, Stephen M.

    2015-01-01

    Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/-mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury. PMID:25786132

  19. The role of placenta growth factor in the hyperoxia-induced acute lung injury in an animal model.

    PubMed

    Zhang, Liang; Yuan, Li-Jie; Zhao, Shuang; Shan, Yu; Wu, Hong-Min; Xue, Xin-Dong

    2015-01-01

    Prolonged exposure to hyperoxia leads to acute lung injury. Alveolar type II cells are main target of hyperoxia-induced lung injury. However, the cellular and molecular mechanisms remain unknown. Here, we aimed to investigate the role of placental growth factor (PLGF) in hyperoxia-induced lung injury. Using experimental hyperoxia-induced lung injury model of neonatal rat and mouse lung epithelial type II cells (MLE-12), we examined the levels of PLGF in bronchoalveolar lavage fluid and in the supernatants of MLE-12 cells. Our results revealed that exogenous PLGF induced hyperoxia-induced lung injury. Furthermore, PLGF triggered a shift of vinculin from insoluble to soluble cell fraction, similar to the observation under hyperoxia stimulation. Moreover, we observed significantly reduced phosphorylation of focal adhesion kinase and increased permeability in MLE-12 cells treated with PLGF. These results suggest that PLGF triggers focal adhesion disassembly in alveolar type II cells via inhibiting the activation of focal adhesion kinase. Our findings reveal a novel role of PLGF in hyperoxia-induced lung injury and provide a potential target for the management of hyperoxia-induced acute lung injury. PMID:25515701

  20. Development of acute lung injury after the combination of intravenous bleomycin and exposure to hyperoxia in rats.

    PubMed Central

    Hay, J G; Haslam, P L; Dewar, A; Addis, B; Turner-Warwick, M; Laurent, G J

    1987-01-01

    Pulmonary toxicity is an important adverse effect of bleomycin treatment. Very little is known of the mechanisms underlying the development of lung injury, especially after intravenous administration, or how it can be modulated. In this study acute lung injury induced by bleomycin has been examined in rats by assessment of alveolar lavage cell profiles, histological examination, and measurement of the total pulmonary extravascular albumin space. Intratracheal instillation of bleomycin 1.5 mg resulted in a severe pneumonitis with influx of inflammatory cells into the alveoli as assessed by alveolar lavage, oedema of the alveolar walls, and up to an eight fold increase in the total pulmonary extravascular albumin space, maximal at 72 hours. Intravenous bleomycin 0.15-5 mg produced no detectable injury when assessed in these ways. Exposure to hyperoxia (40-90%) after intravenous bleomycin, however, induced lung injury similar to that produced by intratracheal bleomycin. A much more severe injury followed administration of intravenous bleomycin after an exposure to hyperoxia, which itself resulted in lung injury; but lung injury was still detectable after bleomycin when the exposure to hyperoxia was insufficient to induce changes in control animals. Lung injury was not observed when the exposure to hyperoxia preceded bleomycin treatment. These results indicate the importance of oxygen in the pathways leading to acute lung injury following intravenous bleomycin. We conclude that exposure to oxygen might induce lung injury during and after bleomycin treatment, and suggest that in these circumstances oxygen therapy should be kept to a minimum. PMID:2443992

  1. A proinflammatory factor in lymphocytes. Its role in the development of acute, non-immunological inflammatory reactions.

    PubMed Central

    Leme, J. C.; Bechara, G. H.; Dos Santos, R. R.

    1976-01-01

    Drug-induced leucopenia renders rats hyporeactive to various inflammatory stimuli. Administration to leucopenic rats of suspensions of lymphocytes, sufficient to apparently correct the induced lymphocytopenia, led to a partial but marked reversal of the inhibited responses. Similar results were observed when lysates of lymphocytes or filtrates of the disintegrated cells were injected. Suspensions of polymorphonuclear granulocytes, on the contrary, were ineffective in producing a reversal of inhibited inflammatory reactions in leucopenic rats. The presence of a proinflammatory factor (LpIF) in lymphocytes, which might be involved in the modulation of acute inflammatory responses is suggested. PMID:971405

  2. Immunological Reconstitution in Children After Completing Conventional Chemotherapy of Acute Lymphoblastic Leukemia is Marked by Impaired B-cell Compartment.

    PubMed

    Koskenvuo, Minna; Ekman, Ilse; Saha, Emmi; Salokannel, Ellinoora; Matomäki, Jaakko; Ilonen, Jorma; Kainulainen, Leena; Arola, Mikko; Lähteenmäki, Päivi Maria

    2016-09-01

    Humoral and cellular immunity were studied in 28 children completing conventional treatment of standard-risk (SR) or intermediate-risk (IR) acute lymphoblastic leukemia (ALL). Both naïve and memory B cells were most severely affected and showed slow recovery during the 2-year follow-up, while the T-cell compartment showed only minor changes. Immunoglobulins and IgG subclasses, components, and antibodies against vaccine-preventable diseases were not significantly affected. In conclusion, immune recovery after conventional chemotherapy for SR and IR ALL is marked by B-cell depletion, but otherwise did not show any severe deficiencies in lymphocyte function. PMID:27163649

  3. Monoclonal Antibody Therapy in Treating Patients With Ovarian Epithelial Cancer, Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-09

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer

  4. Knockdown of Burton's tyrosine kinase confers potent protection against sepsis-induced acute lung injury.

    PubMed

    Zhou, Panyu; Ma, Bing; Xu, Shuogui; Zhang, Shijie; Tang, Hongtai; Zhu, Shihui; Xiao, Shichu; Ben, Daofeng; Xia, Zhaofan

    2014-11-01

    Sepsis is a common and critical complication in surgical patients that often leads to multiple organ failure syndrome (MOFS), including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Despite intensive supportive care and treatment modalities, the mortality of these patients remains high. In this study, we investigated the role of Burton's tyrosine kinase (BTK), a member of the Btk/Tec family of cytoplasmic tyrosine kinases, in the pathogenesis of sepsis, and evaluated the protective effect of in vivo Btk RNA interference in a mouse model of cecal ligation and puncture (CLP)-induced sepsis. After intratracheal injection of Btk siRNA, the mice were then subjected to CLP to induce sepsis. The results demonstrated that this approach conferred potent protection against sepsis-induced ALI, as evidenced by a significant reduction in pathological scores, epithelial cell apoptosis, pulmonary edema, vascular permeability, and the expression of inflammatory cytokines and neutrophil infiltration in the lung tissues of septic mice. In addition, RNA interference of Btk significantly suppressed p-38 and iNOS signaling pathways in transduced alveolar macrophages in vitro. These results identify a novel role for BTK in lethal sepsis and provide a potential new therapeutic approach to sepsis and ALI. PMID:24906236

  5. [Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO)].

    PubMed

    Okazaki, Hitoshi

    2013-05-01

    In recent years, much attention has been paid to respiratory complications of transfusion. Transfusion related acute lung injury (TRALI) is defined as an acute lung injury that is temporally associated with blood transfusion. TRALI is one of the leading causes of mortality. Although the etiology of TRALI is not fully understood, one of its main causes is thought to be anti-leukocyte antibodies, such as HLA antibody or HNA antibody. A precautionary male-predominant plasma strategy has been implemented in many developed countries, which has resulted in considerable achievements in reducing the incidence of TRALI. Meanwhile, transfusion-associated circulatory overload (TACO) has emerged as a major differential diagnosis of TRALI. TACO is a well-known complication of transfusion, which has been considered not as a side effect of transfusion but a result of erroneous medical practice. It has long been an under-reported complication of transfusion and has not been investigated scientifically. Recent data on transfusion mortality from the Food and Drug Administration revealed that TACO was the second highest cause of death in the United States. Our data also suggested a steep increase in the reported cases of TACO in Japan. Precautionary measures should also be implemented for this emerging complication. PMID:23947178

  6. Disparate rates of acute rejection and donor-specific antibodies among high-immunologic risk renal transplant subgroups receiving antithymocyte globulin induction.

    PubMed

    Patel, Samir J; Suki, Wadi N; Loucks-DeVos, Jennifer; Graviss, Edward A; Nguyen, Duc T; Knight, Richard J; Kuten, Samantha A; Moore, Linda W; Teeter, Larry D; Gaber, Lillian W; Gaber, A Osama

    2016-08-01

    Lymphocyte-depleting induction lowers acute rejection (AR) rates among high-immunologic risk (HIR) renal transplant recipients, including African Americans (AAs), retransplants, and the sensitized. It is unclear whether different HIR subgroups experience similarly low rates of AR. We aimed to describe the incidence of AR and de novo donor-specific antibody (dnDSA) among HIR recipients categorized by age, race, or donor type. All received antithymocyte globulin (ATG) induction and triple maintenance immunosuppression. A total of 464 HIR recipients from 2007 to 2014 were reviewed. AR and dnDSA rates at 1 year for the entire population were 14% and 27%, respectively. AR ranged from 6.7% among living donor (LD) recipients to 30% in younger AA deceased donor (DD) recipients. De novo donor-specific antibody at 1 year ranged from 7% in older non-AA LD recipients to 32% in AAs. AA race remained as an independent risk factor for AR among DD recipients and for dnDSA among all HIR recipients. Development of both AR and dnDSA within the first year was associated with a 54% graft survival at 5 years and was an independent risk factor for graft loss. Despite utilization of recommended immunosuppression for HIR recipients, substantial disparities exist among subgroups, warranting further consideration of individualized immunosuppression in certain HIR subgroups. PMID:27196395

  7. Effects of Different Tidal Volume Ventilation on Paraquat-Induced Acute Lung Injury in Piglets

    PubMed Central

    Lan, Chao; Wang, Jinzhu; Li, Li; Li, Haina; Li, Lu; Su, Qianqian; Che, Lu; Liu, Lanping; Di, Min

    2015-01-01

    Background The aim of this study was to explore the effects of different tidal volume (VT) ventilation on paraquat-induced acute lung injury or acute respiratory distress syndrome (ALI/ARDS) in piglets. Material/Methods We developed ALI/ARDS models in piglets by intraperitoneal injection of paraquat (PQ). The piglets were randomly divided into three groups: small VT group (VT=6 ml/kg, n=6), middle VT group (VT=10 ml/kg, n=6), and large VT group (VT=15 ml/kg, n=6), with the positive end-expiratory pressure (PEEP) set as 10 cmH2O. The hemodynamics were monitored by pulse-indicated continuous cardiac output (PiCCO) and the airway pressure changes and blood gas analysis indexes were recorded at different time points. The pathological changes were observed by lung puncture. Results The piglets showed ALI/ARDS in 4.5±0.8 hours after PQ intraperitoneal injection. PH, PaO2 and oxygenation indexes in the three groups all decreased after modeling success compared with baseline, and PaCO2 increased significantly. PH in the small VT group decreased most obviously after ventilation for 6 hours. PaO2 and oxygenation indexes in the small VT group showed the most obvious increase after ventilation for 2 hours and were much higher than the other two groups after ventilation for 6 hours. PaCO2 increased gradually after mechanical ventilation and the small VT group showed most obvious increase. The ELWI increased obviously after ventilation for 2 hours and then the small VT group clearly decreased. PIP and plateau pressure (Pplat) in the small VT group decreased gradually and in the middle and large VT group they increased after ventilation. The lung histopathology showed that the large VT group had the most severe damage and the small VT group had only minimal damage. Conclusions Small tidal volume ventilation combined with PEEP could alleviate the acute lung injury induced by paraquat and improve oxygenation. PMID:25671690

  8. Initial Trophic vs Full Enteral Feeding in Patients With Acute Lung Injury

    PubMed Central

    2013-01-01

    Context The amount of enteral nutrition patients with acute lung injury need is unknown. Objective To determine if initial lower-volume trophic enteral feeding would increase ventilator-free days and decrease gastrointestinal intolerances compared with initial full enteral feeding. Design, Setting, and Participants The EDEN study, a randomized, open-label, multicenter trial conducted from January 2, 2008, through April 12, 2011. Participants were 1000 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Interventions Participants were randomized to receive either trophic or full enteral feeding for the first 6 days. After day 6, the care of all patients who were still receiving mechanical ventilation was managed according to the full feeding protocol. Main Outcome Measures Ventilator-free days to study day 28. Results Baseline characteristics were similar between the trophic-feeding (n=508) and full-feeding (n=492) groups. The full-feeding group received more enteral calories for the first 6 days, about 1300 kcal/d compared with 400 kcal/d (P<.001). Initial trophic feeding did not increase the number of ventilator-free days (14.9 [95% CI, 13.9 to 15.8] vs 15.0 [95% CI, 14.1 to 15.9]; difference, −0.1 [95% CI, −1.4 to 1.2]; P=.89) or reduce 60-day mortality (23.2% [95% CI, 19.6% to 26.9%] vs 22.2% [95% CI, 18.5% to 25.8%]; difference, 1.0% [95% CI, −4.1% to 6.3%]; P=77) compared with full feeding. There were no differences in infectious complications between the groups. Despite receiving more prokinetic agents, the full-feeding group experienced more vomiting (2.2% vs 1.7% of patient feeding days; P=.05), elevated gastric residual volumes (4.9% vs 2.2% of feeding days; P<.001), and constipation (3.1% vs 2.1% of feeding days; P=.003). Mean plasma glucose values and average hourly

  9. Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro.

    PubMed

    Tao, Weiwei; Su, Qiang; Wang, Hanqin; Guo, Shen; Chen, Yanyan; Duan, Jinao; Wang, Shumin

    2015-07-01

    Platycodin D (PLD) is the major triterpene saponin in the root of Platycodon grandiflorum (Jacq.) with various pharmacological activities. The purpose of the present study was to evaluate the protective effects and possible mechanisms of PLD on acute lung injury (ALI) both in vivo and in vitro. In vivo, we used two ALI models, lipopolysaccharide (LPS)-induced ALI and bleomycin (BLE)-induced ALI to evaluate the protective effects and possible mechanisms of PLD. Female BALB/c mice were randomly divided into the following groups: control group, LPS group, LPS plus pre-treatment with dexamethasone (2 mg/kg) group, LPS plus pre-treatment with PLD groups (50 mg/kg, 100 mg/kg), LPS plus post-treatment with dexamethasone (2 mg/kg) group, LPS plus post-treatment with PLD groups (50 mg/kg, 100 mg/kg), BLE group, BLE plus pre-treatment with dexamethasone (2 mg/kg) group, BLE plus pre-treatment with PLD groups (50 mg/kg, 100 mg/kg), BLE plus post-treatment with dexamethasone (2 mg/kg) group, and BLE plus post-treatment with PLD groups (50 mg/kg, 100 mg/kg). PLD was orally administered before or after LPS or BLE challenge with mice. Mice were sacrificed, and lung tissues and bronchoalveolar fluid (BALF) were prepared for further analysis. Our results showed that PLD significantly decreased lung wet-to-dry weight ratio (lung W/D weight ratio), total leukocyte number and neutrophil percentage in the BALF, and myeloperoxidase (MPO) activity of lung in a dose-dependent manner. Besides, cytokine levels, including interleukin (IL)-6, tumor neurosis factor (TNF)-α were also found significantly inhibited in BALF. Furthermore, PLD effectively inhibited the expressions of nuclear factor κB (NF-κB), Caspase-3 and Bax in the lung tissues, as well as restored the expression of Bcl-2 in the lungs and improved the superoxide dismutase (SOD) activity in BALF. In vitro, we used LPS-challenged cell model to evaluate the protective effects and possible mechanisms of PLD. MLE-12 cells were

  10. Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways.

    PubMed

    Li, Kehan; Yang, Jianxue; Han, Xuechang

    2016-05-01

    High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play important roles in the development of sepsis-induced acute lung injury (ALI). Ketamine is considered to confer protective effects on ALI during sepsis. In this study, we investigated the effects of ketamine on HMGB1-RAGE activation in a rat model of sepsis-induced ALI. ALI was induced in wild type (WT) and RAGE deficient (RAGE(-/-)) rats by cecal ligation and puncture (CLP) or HMGB1 to mimic sepsis-induced ALI. Rats were randomly divided to six groups: sham-operation+normal saline (NS, 10mL/kg), sham-operation+ketamine (10mg/kg), CLP/HMGB1+NS (10mL/kg), CLP/HMGB1+ketamine (5mg/kg), CLP/HMGB1+ketamine (7.5mg/kg), and CLP/HMGB1+ketamine (10mg/kg) groups. NS and ketamine were administered at 3 and 12h after CLP/HMGB1 via intraperitoneal injection. Pathological changes of lung, inflammatory cell counts, expression of HMGB1and RAGE, and concentrations of various inflammatory mediators in bronchoalveolar lavage fluids (BALF) and lung tissue were then assessed. Nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in the lung were also evaluated. CLP/HMGB1 increased the wet to dry weight ratio and myeloperoxidase activity in lung, the number of total cells, neutrophils, and macrophages in the BALF, and inflammatory mediators in the BALF and lung tissues. Moreover, expression of HMGB1and RAGE in lung tissues was increased after CLP. Ketamine inhibited all the above effects. It also inhibited the activation of IκB-α, NF-κB p65, and MAPK. Ketamine protects rats against HMGB1-RAGE activation in a rat model of sepsis-induced ALI. These effects may partially result from reductions in NF-κB and MAPK. PMID:26945830

  11. Traditional Chinese medicine, Qing Ying Tang, ameliorates the severity of acute lung injury induced by severe acute pancreatitis in rats via the upregulation of aquaporin-1

    PubMed Central

    GAO, ZHENMING; XU, JUNFENG; SUN, DEGUANG; ZHANG, RIXIN; LIANG, RUI; WANG, LIMING; FAN, RONG

    2014-01-01

    Aquaporin-1 (AQP-1) is expressed in lung endothelial cells and regulates water transport; thus, AQP-1 plays an important role in a number of edema-associated lung diseases. Qing Yin Tang (QYT), a traditional Chinese medicine, has been shown to effectively reduce the mortality rate of acute lung injury (ALI) induced by severe acute pancreatitis (SAP). The current study aimed to investigate the detailed mechanisms underlying the effects of QYT on ALI induced by SAP, particularly the effects on the expression levels of AQP-1 in the lung tissue. ALI was established in Wister rats who were subsequently divided into four groups: SHAM, ALI, dexamethasone (DEX) and QYT groups (n=8 per group). In the QYT group, 20 ml/kg QYT was administered by gavage immediately following the induction of SAP. Blood and lung tissues were collected 8 h following the induction of pancreatitis. The lung wet/dry ratio, as well as the levels of blood gases, serum amylase and tumor necrosis factor-α (TNF-α), were measured at 4, 8 and 12 h following SAP-associated ALI induction surgery. The expression levels of AQP-1 in the lung tissue were detected by quantitative polymerase chain reaction, immunohistochemistry and western blot analysis. No statistically significant differences were observed with regard to the levels of serum amylase, wet/dry ratio, partial pressure of oxygen, serum TNF-α and pathological changes in the pulmonary tissue between the QYT and DEX groups; however, a statistically significant difference was observed when compared with the ALI group. The expression levels of AQP-1 significantly increased (P<0.05) and lung edema was alleviated in the QYT and DEX groups, when compared with ALI group. Therefore, the expression level of AQP-1 is associated with pulmonary edema. QYT protects the lungs from injury induced by SAP via the upregulation of AQP-1, which suppresses TNF-α expression. PMID:25371738

  12. Traditional Chinese medicine, Qing Ying Tang, ameliorates the severity of acute lung injury induced by severe acute pancreatitis in rats via the upregulation of aquaporin-1.

    PubMed

    Gao, Zhenming; Xu, Junfeng; Sun, Deguang; Zhang, Rixin; Liang, Rui; Wang, Liming; Fan, Rong

    2014-12-01

    Aquaporin-1 (AQP-1) is expressed in lung endothelial cells and regulates water transport; thus, AQP-1 plays an important role in a number of edema-associated lung diseases. Qing Yin Tang (QYT), a traditional Chinese medicine, has been shown to effectively reduce the mortality rate of acute lung injury (ALI) induced by severe acute pancreatitis (SAP). The current study aimed to investigate the detailed mechanisms underlying the effects of QYT on ALI induced by SAP, particularly the effects on the expression levels of AQP-1 in the lung tissue. ALI was established in Wister rats who were subsequently divided into four groups: SHAM, ALI, dexamethasone (DEX) and QYT groups (n=8 per group). In the QYT group, 20 ml/kg QYT was administered by gavage immediately following the induction of SAP. Blood and lung tissues were collected 8 h following the induction of pancreatitis. The lung wet/dry ratio, as well as the levels of blood gases, serum amylase and tumor necrosis factor-α (TNF-α), were measured at 4, 8 and 12 h following SAP-associated ALI induction surgery. The expression levels of AQP-1 in the lung tissue were detected by quantitative polymerase chain reaction, immunohistochemistry and western blot analysis. No statistically significant differences were observed with regard to the levels of serum amylase, wet/dry ratio, partial pressure of oxygen, serum TNF-α and pathological changes in the pulmonary tissue between the QYT and DEX groups; however, a statistically significant difference was observed when compared with the ALI group. The expression levels of AQP-1 significantly increased (P<0.05) and lung edema was alleviated in the QYT and DEX groups, when compared with ALI group. Therefore, the expression level of AQP-1 is associated with pulmonary edema. QYT protects the lungs from injury induced by SAP via the upregulation of AQP-1, which suppresses TNF-α expression. PMID:25371738

  13. Eupatorium lindleyanum DC. flavonoids fraction attenuates lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Chu, Chunjun; Yao, Shi; Chen, Jinglei; Wei, Xiaochen; Xia, Long; Chen, Daofeng; Zhang, Jian

    2016-10-01

    Eupatorium lindleyanum DC., "Ye-Ma-Zhui" called by local residents in China, showed anti-inflammatory activity and is used to treat tracheitis. We had isolated and identified the flavonoids, diterpenoids and sesquiterpenes compounds from the herb. In the present study, we evaluated the protective effects of the flavonoids fraction of E. lindleyanum (EUP-FLA) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible underlying mechanisms of action. EUP-FLA could significantly decrease lung wet-to-dry weight (W/D) ratio, nitric oxide (NO) and protein concentration in BALF, lower myeloperoxidase (MPO) activity, increase superoxide dismutase (SOD) activity and down-regulate the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). Additionally, EUP-FLA attenuated lung histopathological changes and significantly reduced complement deposition with decreasing the levels of Complement 3 (C3) and Complement 3c (C3c) in serum. These results demonstrated that EUP-FLA may attenuate LPS-induced ALI via reducing productions of pro-inflammatory mediators, decreasing the level of complement and affecting the NO, SOD and MPO activity. PMID:27398612

  14. VEGF-D promotes pulmonary oedema in hyperoxic acute lung injury.

    PubMed

    Sato, Teruhiko; Paquet-Fifield, Sophie; Harris, Nicole C; Roufail, Sally; Turner, Debra J; Yuan, Yinan; Zhang, You-Fang; Fox, Stephen B; Hibbs, Margaret L; Wilkinson-Berka, Jennifer L; Williams, Richard A; Stacker, Steven A; Sly, Peter D; Achen, Marc G

    2016-06-01

    Leakage of fluid from blood vessels, leading to oedema, is a key feature of many diseases including hyperoxic acute lung injury (HALI), which can occur when patients are ventilated with high concentrations of oxygen (hyperoxia). The molecular mechanisms driving vascular leak and oedema in HALI are poorly understood. VEGF-D is a protein that promotes blood vessel leak and oedema when overexpressed in tissues, but the role of endogenous VEGF-D in pathological oedema was unknown. To address these issues, we exposed Vegfd-deficient mice to hyperoxia. The resulting pulmonary oedema in Vegfd-deficient mice was substantially reduced compared to wild-type, as was the protein content of bronchoalveolar lavage fluid, consistent with reduced vascular leak. Vegf-d and its receptor Vegfr-3 were more highly expressed in lungs of hyperoxic, versus normoxic, wild-type mice, indicating that components of the Vegf-d signalling pathway are up-regulated in hyperoxia. Importantly, VEGF-D and its receptors were co-localized on blood vessels in clinical samples of human lungs exposed to hyperoxia; hence, VEGF-D may act directly on blood vessels to promote fluid leak. Our studies show that Vegf-d promotes oedema in response to hyperoxia in mice and support the hypothesis that VEGF-D signalling promotes vascular leak in human HALI. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID:26924464

  15. Protective effects of fenofibrate against acute lung injury induced by intestinal ischemia/reperfusion in mice

    PubMed Central

    Zhu, Qiankun; He, Guizhen; Wang, Jie; Wang, Yukang; Chen, Wei

    2016-01-01

    This experiment was conducted to evaluate whether pretreatment with fenofibrate could mitigate acute lung injury (ALI) in a mice model of intestinal ischemia/reperfusion (I/R). Male C57BL/6 mice were randomly assigned into three groups (n = 6): sham, intestinal I/R + vehicle, and intestinal I/R + fenofibrate. Intestinal I/R was achieved by clamping the superior mesenteric artery. Fenofibrate (100 mg/kg) or equal volume of vehicle was injected intraperitoneally 60 minutes before the ischemia. At the end of experiment, measurement of pathohistological score, inflammatory mediators and other markers were performed. In addition, a 24-hour survival experiment was conducted in intestinal I/R mice treated with fenofibrate or vehicle. The chief results were as anticipated. Pathohistological evaluation indicated that fenofibrate ameliorated the local intestine damage and distant lung injury. Pretreatment with fenofibrate significantly decreased inflammatory factors in both the intestine and the lung. Consistently, renal creatine levels and hepatic ALT levels were significantly decreased in the fenofibrate group. Moreover, serum systemic inflammatory response indicators were significantly alleviated in the fenofibrate group. In addition, fenofibrate administration significantly improved the survival rate. Collectively, our data indicated that pretreatment with fenofibrate prior to ischemia attenuated intestinal I/R injury and ALI. PMID:26902261

  16. PcrV antibody protects multi-drug resistant Pseudomonas aeruginosa induced acute lung injury.

    PubMed

    Wang, Qin; Li, Huayin; Zhou, Jian; Zhong, Ming; Zhu, Duming; Feng, Nana; Liu, Fanglei; Bai, Chunxue; Song, Yuanlin

    2014-03-01

    Blocking PcrV, an essential component of the Type III secretion system (TTSS), has demonstrated efficacy against Pseudomonas aeruginosa infections. However, most of the results came from laboratory strains. Whether it is applicable to clinically isolated multi-drug resistant (MDR) strains is unknown. In this study we investigated the expression level of TTSS in clinically isolated MDR P. aeruginosa strains and the effects of anti-PcrV antibody on MDR isolate induced acute lung injury (ALI). The expression level of TTSS was quantified in 53 isolates including 25 MDR strains and 28 susceptible strains. We investigated the effect of anti-PcrV antibody through a murine model induced by instillation of a MDR strain into the left lung through trachea. Our results showed that the expression level of TTSS in MDR strains is comparable to susceptible strains. Anti-PcrV ensured the survival of challenged mice, reduced the bacteria numbers and attenuated lung inflammation and injury. This study proved that anti-PcrV may be a potentially effective strategy against MDR P. aeruginosa induced ALI. PMID:24418353

  17. Recruitment maneuver: RAMP versus CPAP pressure profile in a model of acute lung injury.

    PubMed

    Riva, D R; Contador, R S; Baez-Garcia, C S N; Xisto, D G; Cagido, V R; Martini, S V; Morales, M M; Rocco, P R M; Faffe, D S; Zin, W A

    2009-10-31

    We examined whether recruitment maneuvers (RMs) with gradual increase in airway pressure (RAMP) provide better outcome than continuous positive airway pressure (CPAP) in paraquat-induced acute lung injury (ALI). Wistar rats received saline intraperitoneally (0.5 mL, CTRL) or paraquat (15 mg/kg, ALI). Twenty-four hours later lung mechanics [static elastance, viscoelastic component of elastance, resistive, viscoelastic and total pressures] were determined before and after recruitment with 40cmH2O CPAP for 40s or 40-s-long slow increase in pressure up to 40cmH2O (RAMP) followed by 0 or 5 cmH2O PEEP. Fractional area of alveolar collapse and PCIII mRNA were determined. All mechanical parameters and the fraction area of alveolar collapse were higher in ALI compared to CTRL. Only RAMP-PEEP maneuver significantly improved lung mechanics and decreased PCIII mRNA expression (53%) compared with ALI, while both RMs followed by PEEP decreased alveolar collapse. In conclusion, in the present experimental ALI model, RAMP followed by 5cm H2O PEEP yields a better outcome. PMID:19712760

  18. Acute response to elastase in sheep lungs measured with Ga-67

    SciTech Connect

    Susskind, H.; Chanana, A.D.; Joel, D.D.; Brill, A.B.; Janoff, A.; Som, P.; Oster, Z.H.

    1984-12-01

    The early inflammatory changes in sheep's lungs were studied with Ga-67 citrate, injected i.v. immediately following intrabronchial instillation of different doses of elastase into the right diaphragmatic lobes of 15 sheep. The elastase-induced lesions in the first five sheep (two received 4000 units; three got 6000) were imaged up to seven times in an 8-day period to measure the temporal changes in the lesion and to select the appropriate imaging time; the other ten sheep (800-8000 units) were imaged once at 52 hr. Localization of Ga-67, as seen on the posterior and right lateral projections, was confined to a well-circumscribed region in the right lung field. The lesion could be detected as early as 4 hr after elastase instillation. It decreased to 60% of its initial area at 4 hr, while the total Ga-67 activity in the sheep remained constant after 52-75 hr. Gallium-67 uptake in the lesion correlated positively with the dose of elastase (r = 0.88, p < 0.001) and with the reduction in perfusion, as determined 4 wk after the elastase instillation (r = 0.66, p < 0.05). Early Ga-67 uptake in inflammatory lung lesions could therefore be used as a reliable predictor of the size of the acute elastase-induced inflammatory reaction, as well as of the sequelae involving the regional vascular supply 4 wk later. 25 references, 5 figures, 2 tables.

  19. Withaferin A attenuates lipopolysaccharide-induced acute lung injury in neonatal rats.

    PubMed

    Gao, S; Li, H; Zhou, X-Q; You, J-B; Tu, D-N; Xia, G; Jiang, J-X; Xin, C

    2015-01-01

    Withaferin A (WFA) is an active compound from Withania somnifera and has been reported to exhibit a variety of pharmacological activities such as anti—inflammatory, immunomodulatory and anti—tumor properties. In the present study, we investigated the potential protective role of WFA on acute lung injury in neonatal rats induced by lipopolysaccharide (LPS). We found that WFA significantly attenuated the pathological changes of lungs induced by LPS injection. Administration with WFA obviously decreased pulmonary neutrophil infiltration accompanied with decreased MPO concentrations. WFA also reduced the expression of pro—inflammatory cytokines including MIP—2, TNF—α, IL—1β and IL—6. Meanwhile, the expression levels of anti—inflammatory mediators such as TGF—β1 and IL—10 were significantly increased following WFA administration. Moreover, WFA protected LPS—treated rats from oxidative damage via up—regulation of TBARS and H2O2 concentrations and down—regulation of ROS contents. Taken together, the present study demonstrated that WFA administration attenuated LPS—induced lung injury through inhibition of inflammatory responses and oxidative stress. PMID:26255139

  20. Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats.

    PubMed

    Zhao, Hongyu; Zhao, Min; Wang, Yu; Li, Fengchun; Zhang, Zhigang

    2016-02-01

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. However, the effects of GA on sepsis-induced acute lung injury (ALI) have not been determined. Tthe aim of this study was to investigate the molecular mechanism involved in the effects of GA against sepsis-induced ALI in rats. We found that GA alleviated sepsis-induced ALI through improvements in various pathological changes, as well as decreases in the lung wet/dry weight ratio and total protein content in bronchoalveolar lavage fluid, and a significant increase in the survival rate of treated rats. Additionally, GA markedly inhibited sepsis-induced pulmonary inflammatory responses. Moreover, we found that treatment with GA inhibited oxidative stress damage and apoptosis in lung tissue induced by ALI. Finally, GA treatment significantly inhibited NF-κ B, JNK and P38 MAPK activation. Our data indicate that GA has a protective effect against sepsis-induced ALI by inhibiting the inflammatory response, damage from oxidative stress, and apoptosis via inactivation of NF-κB and MAPK signaling pathways, providing a molecular basis for a new medical treatment for sepsis-induced ALI. PMID:26385569

  1. Systemic response induced by Scorpaena plumieri fish venom initiates acute lung injury in mice.

    PubMed

    Boletini-Santos, Douglas; Komegae, Evilin Naname; Figueiredo, Suely G; Haddad, Vidal; Lopes-Ferreira, Mônica; Lima, Carla

    2008-03-15

    Scorpaena plumieri venomous fish inflicted severe injuries in humans characterized by systemic effects and cardiovascular abnormalities. Although cardiotoxic and hypotensive effects induced in rats by this venom have been studied, little is known about their effect on bronchial epithelial permeability and airway inflammation in mice. The primary goal of this study was to determine whether the intraplantar or intraperitoneal injection of S. plumieri venom results in systemic response, and whether this event initiates acute lung injury. We found that BALB/c mice developed neutrophilic infiltrates, areas of lung hemorrhage and alveolar macrophage activation within 24h after injection with S. plumieri venom. These histopathological changes were associated with an early increase in BAL fluid protein and early induction of cytokines, chemokines and matrix metalloproteinases, followed by a later increase in BAL fluid neutrophils. These findings provide clear evidence that the injection of S. plumieri venom in footpad or peritoneal cavity of mice results in venom deposition in the airway and initiates a sustained inflammatory response in the lungs. PMID:18191167

  2. On the significance of estimating thallium lung uptake images in patients with acute myocardial infarction

    SciTech Connect

    Tanaka, T.; Kimata, S.; Hirosawa, K.; Kusakabe, K.; Shigeta, T.; Ito, Y.; Shimizu, Y.; Tanaka, T.; Abe, M.; Matsuda, M.

    1984-01-01

    To determine whether thallium lung uptake images (TLI) can be used as a noninvasive method to estimate any of hemodynamic changes in patients (pts) with acute myocardial infarction (AMI) TLI were evaluated in 23 pts with AMI. All pts underwent multigated blood pool imaging and cardiac catheterization. TLI were estimated by comparing the intensity of T1-201 activity in the lower right lung with maximal myocardial count (thallium lung heart ratio; LHR). Pts with AMI were classified to 3 grades according to LHR. The classifications were hemodynamically significant. The specificity of LHR <0.6 for mPw <18mmHg was 100% (10/10). The specificity of LHR greater than or equal to 0.8 for mPw greater than or equal to 18mmHg was 85% (11/13) and for EF greater than or equal to 30% was 100% (13/13). The pts with LHR 0.8 showed high mortality (4/9) and high morbidity (all survivors were in NYHA class 2-3 and receiving digitalis and diuretics). TLI were easily obtained after routine T1-myocardial imaging, i.e. another 5 minutes imaging yielded clinically useful information for separating high and low-risk groups of pts with AMI.

  3. Pulmonary clearance of radiotracers after positive end-expiratory pressure or acute lung injury

    SciTech Connect

    Barrowcliffe, M.P.; Zanelli, G.D.; Jones, J.G.

    1989-01-01

    In anesthetized rabbits we measured clearance from lung to blood of eight aerosolized technetium-99m-labeled compounds: diethylenetriaminepentaacetate (99mTc-DTPA); cytochrome c; myoglobin; a myoglobin polymer; albumin; and anionic, cationic, and neutral dextrans of equivalent molecular size. We investigated the effect of applying positive end-expiratory pressure (PEEP) and, on a subsequent occasion, of injecting oleic acid intravenously to produce acute lung injury on the pulmonary clearance rate. Base-line clearance rates were monoexponential and varied with the molecular weights of the radiotracers. For each tracer the rate of clearance was increased a similar degree by either PEEP or oleic acid. However, with PEEP, clearance remained monoexponential, whereas after oleic acid, smaller molecular-weight radiotracers had multiexponential clearance curves. This suggests that after oleic acid the alveolar epithelium breaks down in a nonuniform fashion. We conclude that differentiation of the effect of PEEP from that of severe lung injury caused by oleic acid is not readily accomplished by either increasing the size of the tracer molecule or by varying the molecular charge.

  4. Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression.

    PubMed

    Galam, Lakshmi; Rajan, Ashna; Failla, Athena; Soundararajan, Ramani; Lockey, Richard F; Kolliputi, Narasaiah

    2016-03-15

    Increasing evidence shows that hyperoxia is a serious complication of oxygen therapy in acutely ill patients that causes excessive production of free radicals leading to hyperoxia-induced acute lung injury (HALI). Our previous studies have shown that P2X7 receptor activation is required for inflammasome activation during HALI. However, the role of P2X7 in HALI is unclear. The main aim of this study was to determine the effect of P2X7 receptor gene deletion on HALI. Wild-type (WT) and P2X7 knockout (P2X7 KO) mice were exposed to 100% O2 for 72 h. P2X7 KO mice treated with hyperoxia had enhanced survival in 100% O2 compared with the WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1β, TNF-α, monocyte chemoattractant protein-1, and IL-6 levels were attenuated in P2X7 KO mice. P2X7 deletion decreased lung edema and alveolar protein content, which are associated with enhanced alveolar fluid clearance. In addition, activation of the inflammasome was suppressed in P2X7-deficient alveolar macrophages and was associated with suppression of IL-1β release. Furthermore, P2X7-deficient alveolar macrophage in type II alveolar epithelial cells (AECs) coculture model abolished protein permeability across mouse type II AEC monolayers. Deletion of P2X7 does not lead to a decrease in epithelial sodium channel expression in cocultures of alveolar macrophages and type II AECs. Taken together, these findings show that deletion of P2X7 is a protective factor and therapeutic target for the amelioration of hyperoxia-induced lung injury. PMID:26747786

  5. Acute Lung Injury and Fibrosis in a Baboon Model of Escherichia coli Sepsis

    PubMed Central

    Keshari, Ravi S.; Silasi-Mansat, Robert; Zhu, Hua; Popescu, Narcis I.; Peer, Glenn; Chaaban, Hala; Lambris, John D.; Polf, Holly; Lupu, Cristina; Kinasewitz, Gary

    2014-01-01

    Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrosis. The pathology of ARDS is complex and poorly understood, and the therapeutic approaches are limited. We used a baboon model of Escherichia coli sepsis that mimics the complexity of human disease to study the pathophysiology of ARDS. We performed extensive biochemical, histological, and functional analyses to characterize the disease progression and the long-term effects of sepsis on the lung structure and function. Similar to humans, sepsis-induced ARDS in baboons displays an early inflammatory exudative phase, with extensive necrosis. This is followed by a regenerative phase dominated by proliferation of type 2 epithelial cells, expression of epithelial-to-mesenchymal transition markers, myofibroblast migration and proliferation, and collagen synthesis. Baboons that survived sepsis showed persistent inflammation and collagen deposition 6–27 months after the acute episodes. Long-term survivors had almost double the amount of collagen in the lung as compared with age-matched control animals. Immunostaining for procollagens showed persistent active collagen synthesis within the fibroblastic foci and interalveolar septa. Fibroblasts expressed markers of transforming growth factor-β and platelet-derived growth factor signaling, suggesting their potential role as mediators of myofibroblast migration and proliferation, and collagen deposition. In parallel, up-regulation of the inhibitors of extracellular proteases supports a deregulated matrix remodeling that may contribute to fibrosis. The primate model of sepsis-induced ARDS mimics the disease progression in humans, including chronic inflammation and long-lasting fibrosis. This model helps our understanding of the pathophysiology of fibrosis and the testing of new therapies. PMID:24066737

  6. Arginase 1: an unexpected mediator of pulmonary capillary barrier dysfunction in models of acute lung injury.

    PubMed

    Lucas, Rudolf; Czikora, Istvàn; Sridhar, Supriya; Zemskov, Evgeny A; Oseghale, Aluya; Circo, Sebastian; Cederbaum, Stephen D; Chakraborty, Trinad; Fulton, David J; Caldwell, Robert W; Romero, Maritza J

    2013-01-01

    The integrity of epithelial and endothelial barriers in the lower airspaces of the lungs has to be tightly regulated, in order to prevent leakage and to assure efficient gas exchange between the alveoli and capillaries. Both G(-) and G(+) bacterial toxins, such as lipopolysaccharide and pneumolysin, respectively, can be released in high concentrations within the pulmonary compartments upon antibiotic treatment of patients suffering from acute respiratory distress syndrome (ARDS) or severe pneumonia. These toxins are able to impair endothelial barrier function, either directly, or indirectly, by induction of pro-inflammatory mediators and neutrophil sequestration. Toxin-induced endothelial hyperpermeability can involve myosin light chain phosphorylation and/or microtubule rearrangement. Endothelial nitric oxide synthase (eNOS) was proposed to be a guardian of basal barrier function, since eNOS knock-out mice display an impaired expression of inter-endothelial junction proteins and as such an increased vascular permeability, as compared to wild type mice. The enzyme arginase, the activity of which can be regulated by the redox status of the cell, exists in two isoforms - arginase 1 (cytosolic) and arginase 2 (mitochondrial) - both of which can be expressed in lung microvascular endothelial cells. Upon activation, arginase competes with eNOS for the substrate l-arginine, as such impairing eNOS-dependent NO generation and promoting reactive oxygen species generation by the enzyme. This mini-review will discuss recent findings regarding the interaction between bacterial toxins and arginase during acute lung injury and will as such address the role of arginase in bacterial toxin-induced pulmonary endothelial barrier dysfunction. PMID:23966993

  7. Antithrombin Attenuates Vascular Leakage via Inhibiting Neutrophil Activation in Acute Lung Injury

    PubMed Central

    Rehberg, Sebastian; Yamamoto, Yusuke; Sousse, Linda E.; Jonkam, Collette; Zhu, Yong; Traber, Lillian D.; Cox, Robert A.; Prough, Donald S.; Traber, Daniel L.; Enkhbaatar, Perenlei

    2014-01-01

    Objective To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury. Design Randomized controlled laboratory experiment. Setting University animal research facility. Subjects Eighteen chronically instrumented sheep. Interventions Following combined burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses. Measurements and Main Results Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12–48 hr: p ≤ 0.001 vs control each) and the deteriorated pulmonary gas exchange (12–48 hr: p < 0.05 vs control each) without increasing the risk of bleeding. Conclusions The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological

  8. Silencing of fas, fas-associated via death domain, or caspase 3 differentially affects lung inflammation, apoptosis, and development of trauma-induced septic acute lung injury.

    PubMed

    Messer, Mirko Philipp; Kellermann, Philipp; Weber, Sascha Jörn; Hohmann, Christoph; Denk, Stephanie; Klohs, Bettina; Schultze, Anke; Braumüller, Sonja; Huber-Lang, Markus Stefan; Perl, Mario

    2013-01-01

    Activation of Fas signaling is a potentially important pathophysiological mechanism in the development of septic acute lung injury (ALI). However, so far the optimal targets within this signaling cascade remain elusive. Thus, we tested the hypothesis that in vivo gene silencing of Fas, Fas-associated via death domain (FADD), or caspase 3 by intratracheal administration of small interfering RNA would ameliorate ALI in a clinically relevant double-hit mouse model of trauma induced septic lung injury. Male C57Bl/6 mice received small interfering (Fas, FADD, caspase 3) or control RNA 24 h before and 12 h after blunt chest trauma or sham procedures. Polymicrobial sepsis was induced by cecal ligation and puncture 24 h after chest trauma. Twelve or 24 h later, lung tissue, plasma, and bronchoalveolar lavage fluid were harvested. During ALI, lung apoptosis (active caspase 3 Western blotting, TUNEL staining) was substantially increased when compared with sham. Silencing of caspase 3 or FADD both markedly reduced pulmonary apoptosis. Fas- and FADD-small interfering RNA administration substantially decreased lung cytokine concentration, whereas caspase 3 silencing did not reduce lung inflammation. In addition, Fas silencing markedly decreased lung neutrophil infiltration. Interestingly, only in response to caspase 3 silencing, ALI-induced lung epithelial barrier dysfunction was substantially improved, and histological appearance was beneficially affected. Taken together, downstream inhibition of lung apoptosis via caspase 3 silencing proved to be superior in mitigating ALI when compared with upstream inhibition of apoptosis via Fas or FADD silencing, even in the presence of additional anti-inflammatory effects. This indicates a major pathophysiological role of lung apoptosis and suggests the importance of other than Fas-driven apoptotic pathways in trauma-induced septic ALI. PMID:23247118

  9. Immunological reactions and respiratory function in wool textile workers.

    PubMed

    Zuskin, E; Kanceljak, B; Mustajbegovic, J; Godnic-Cvar, J; Schachter, E N

    1995-09-01

    Immunological status and respiratory function were studied in a group of 64 wool textile workers (52 women and 12 men). A group of 46 workers not exposed to wool dust served as a control for the respiratory symptoms and immunologic testing. Skin testing was performed with different wool allergens (domestic and Australian) as well as with common allergens. Ventilatory capacity was measured in wool workers on Mondays before and after the work shift. The prevalence of positive skin tests to all allergens was higher in wool than in control workers, although the difference was statistically significant only for washed domestic wool (wool workers: 42.2%; control workers: 19.6%; p < 0.05). Increased serum IgE levels were more frequent in wool (26.6%) than in control workers (3.1%) (p < 0.01). In wool textile workers there was a high prevalence of acute and chronic respiratory symptoms. Significant across-shift reductions in ventilatory capacity tests, as well as abnormal baseline lung function, were recorded in wool textile workers. Individual data demonstrated that many of the wool workers had FEF25 lower than 70% of predicted. In general, the prevalence of symptoms and the lung function abnormalities did not correlate with the results of specific (wool) skin tests. Our data indicate that exposure to wool dust in some workers may be associated with the development of acute and chronic respiratory symptoms and impairment of lung function. Immunologic abnormalities, although frequent in this group, do not appear to be associated with the severity of these changes. PMID:7485197

  10. Functional characterisation of human pulmonary monocyte-like cells in lipopolysaccharide-mediated acute lung inflammation

    PubMed Central

    2014-01-01

    Background We have previously reported the presence of novel subpopulations of pulmonary monocyte-like cells (PMLC) in the human lung; resident PMLC (rPMLC, HLA-DR+CD14++CD16+cells) and inducible PMLC (iPMLC, HLA-DR+CD14++CD16- cells). iPMLC are significantly increased in bronchoalveolar lavage (BAL) fluid following inhalation of lipopolysaccharide (LPS). We have carried out the first functional evaluation of PMLC subpopulations in the inflamed lung, following the isolation of these cells, and other lineages, from BAL fluid using novel and complex protocols. Methods iPMLC, rPMLC, alveolar macrophages (AM), neutrophils, and regulatory T cells were quantified in BAL fluid of healthy subjects at 9 hours post-LPS inhalation (n = 15). Cell surface antigen expression by iPMLC, rPMLC and AM and the ability of each lineage to proliferate and to undergo phagocytosis were investigated using flow cytometry. Basal cytokine production by iPMLC compared to AM following their isolation from BAL fluid and the responsiveness of both cell types following in vitro treatment with the synthetic corticosteroid dexamethasone were assessed. Results rPMLC have a significantly increased expression of mature macrophage markers and of the proliferation antigen Ki67, compared to iPMLC. Our cytokine data revealed a pro-inflammatory, corticosteroid-resistant phenotype of iPMLC in this model. Conclusions These data emphasise the presence of functionally distinct subpopulations of the monocyte/macrophage lineage in the human lung in experimental acute lung inflammation. PMID:24684897

  11. Clinical and prognostic significance of lung thallium uptake on rest imaging in acute myocardial infarction

    SciTech Connect

    Jain, D.; Lahiri, A.; Raftery, E.B. )

    1990-01-15

    Exercise-induced pulmonary uptake of thallium-201 in patients with ischemic heart disease is probably due to transient pulmonary edema and left ventricular failure induced by exercise. The significance of increased lung uptake of thallium-201 at rest after acute myocardial infarction (AMI) has not been described. Ninety-six patients admitted with chest pain for suspected AMI or unstable angina underwent thallium-201 imaging at rest. Using conventional diagnostic criteria, 62 had AMI, 12 had unstable angina and 22 had neither. Increased lung uptake of thallium-201 was present in 24 of the total 96 (25%) patients, 20 of the 62 (32%) patients with AMI and 4 of 34 (13%) patients with no evidence of infarction. In the AMI group, those with increased lung thallium-201 uptake had a higher mean +/- standard deviation segmental thallium-201 defect score (22 +/- 7 vs 12 +/- 8, p less than 0.0001), lower ejection fraction (35 +/- 14 vs 49 +/- 14%, p less than 0.002), higher peak creatine kinase levels (2,410 +/- 1,247 vs 1,496 +/- 1,228 IU/liter, p less than 0.01), higher wall motion abnormality score (25 +/- 13 vs 13 +/- 12, p less than 0.0001), increased incidence of clinical in-hospital heart failure (15 of 20 vs 7 of 42, p less than 0.0001) and higher short-term mortality (4 of 20 vs 1 of 42, p less than 0.02) compared to those without increased lung thallium-201 uptake.

  12. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid.

    PubMed

    Fisher, Bernard J; Kraskauskas, Donatas; Martin, Erika J; Farkas, Daniela; Wegelin, Jacob A; Brophy, Donald; Ward, Kevin R; Voelkel, Norbert F; Fowler, Alpha A; Natarajan, Ramesh

    2012-07-01

    Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis. PMID

  13. Lack of cyclophilin D protects against the development of acute lung injury in endotoxemia.

    PubMed

    Fonai, Fruzsina; Priber, Janos K; Jakus, Peter B; Kalman, Nikoletta; Antus, Csenge; Pollak, Edit; Karsai, Gergely; Tretter, Laszlo; Sumegi, Balazs; Veres, Balazs

    2015-12-01

    Sepsis caused by LPS is characterized by an intense systemic inflammatory response affecting the lungs, causing acute lung injury (ALI). Dysfunction of mitochondria and the role of reactive oxygen (ROS) and nitrogen species produced by mitochondria have already been proposed in the pathogenesis of sepsis; however, the exact molecular mechanism is poorly understood. Oxidative stress induces cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT), leading to organ failure in sepsis. In previous studies mPT was inhibited by cyclosporine A which, beside CypD, inhibits cyclophilin A, B, C and calcineurin, regulating cell death and inflammatory pathways. The immunomodulatory side effects of cyclosporine A make it unfavorable in inflammatory model systems. To avoid these uncertainties in the molecular mechanism, we studied endotoxemia-induced ALI in CypD(-/-) mice providing unambiguous data for the pathological role of CypD-dependent mPT in ALI. Our key finding is that the loss of this essential protein improves survival rate and it can intensely ameliorate endotoxin-induced lung injury through attenuated proinflammatory cytokine release, down-regulation of redox sensitive cellular pathways such as MAPKs, Akt, and NF-κB and reducing the production of ROS. Functional inhibition of NF-κB was confirmed by decreased expression of NF-κB-mediated proinflammatory genes. We demonstrated that impaired mPT due to the lack of CypD reduces the severity of endotoxemia-induced lung injury suggesting that CypD specific inhibitors might have a great therapeutic potential in sepsis-induced organ failure. Our data highlight a previously unknown regulatory function of mitochondria during inflammatory response. PMID:26385159

  14. Enhanced Resolution of Hyperoxic Acute Lung Injury as a result of Aspirin Triggered Resolvin D1 Treatment.

    PubMed

    Cox, Ruan; Phillips, Oluwakemi; Fukumoto, Jutaro; Fukumoto, Itsuko; Parthasarathy, Prasanna Tamarapu; Arias, Stephen; Cho, Young; Lockey, Richard F; Kolliputi, Narasaiah

    2015-09-01

    Acute lung injury (ALI), which presents as acute respiratory failure, is a major clinical problem that requires aggressive care, and patients who require prolonged oxygen exposure are at risk of developing this disease. Although molecular determinants of ALI have been reported, the molecules involved in disease catabasis associated with oxygen toxicity have not been well studied. It has been reported that lung mucosa is rich in omega-3 fatty acid dicosahexanoic acid (DHA), which has antiinflammatory properties. Aspirin-triggered resolvin D1 (AT-RvD1) is a potent proresolution metabolite of DHA that can curb the inflammatory effects in various acute injuries, yet the effect of AT-RvD1 on hyperoxic acute lung injury (HALI) or in the oxygen toxicity setting in general has not been investigated. The effects of AT-RvD1 on HALI were determined for the first time in 8- to 10-week-old C57BL/6 mice that were exposed to hyperoxia (≥95% O2) for 48 hours. Mice were given AT-RvD1 (100 ng) in saline or a saline vehicle for 24 hours in normoxic (≈21% O2) conditions after hyperoxia. Lung tissue and bronchoalveolar lavage (BAL) fluid were collected for analysis associated with proinflammatory signaling and lung inflammation. AT-RvD1 treatment resulted in reduced oxidative stress, increased glutathione production, and significantly decreased tissue inflammation. AT-RvD1 treatment also significantly reduced the lung wet/dry ratio, protein in BAL fluid, and decreased apoptotic and NF-κB signaling. These results show that AT-RvD1 curbs oxygen-induced lung edema, permeability, inflammation, and apoptosis and is thus an effective therapy for prolonged hyperoxia exposure in this murine model. PMID:25647402

  15. Phenotype of NK Cells Determined on the Basis of Selected Immunological Parameters in Children Treated due to Acute Lymphoblastic Leukemia.

    PubMed

    Koltan, Sylwia; Debski, Robert; Koltan, Andrzej; Grzesk, Elzbieta; Tejza, Barbara; Eljaszewicz, Andrzej; Gackowska, Lidia; Kubicka, Malgorzata; Kolodziej, Beata; Kurylo-Rafinska, Beata; Kubiszewska, Izabela; Wiese, Malgorzata; Januszewska, Milena; Michalkiewicz, Jacek; Wysocki, Mariusz; Styczynski, Jan; Grzesk, Grzegorz

    2015-12-01

    Acute lymphoblastic leukemia (ALL) is the most frequent pediatric malignancy. The chemotherapy for ALL is associated with a profound secondary immune deficiency.We evaluated the number and phenotype of natural killer (NK) cells at diagnosis, after the intensive chemotherapy and following the completion of the entire treatment for patients with ALL. The fraction, absolute number, and percentage of NK cells expressing interferon-γ were determined in full blood samples. The fraction of NK cells expressing CD158a, CD158b, perforin, A, B, and K granzymes was examined in isolated NK cells.We have shown that patients assessed at ALL diagnosis showed significantly lower values of the fraction of NK cells and percentage of NK cells with the granzyme A expression. Additionally, the absolute number of NK cells, the expression of CD158a, CD158b, perforin, and granzyme A were significantly lower in patients who completed intensive chemotherapy. Also, there was a significantly higher fraction of NK cells expressing granzyme K in patients who completed the therapy.Abnormalities of NK cells were found at all stages of the treatment; however, the most pronounced changes were found at the end of intensive chemotherapy. PMID:26717380

  16. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    SciTech Connect

    Malaviya, Rama; Venosa, Alessandro; Hall, LeRoy; Gow, Andrew J.; Sinko, Patrick J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-12-15

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute

  17. Dosimetric correlations of acute esophagitis in lung cancer patients treated with radiotherapy

    SciTech Connect

    Takeda, Ken . E-mail: takedak41@yahoo.co.jp; Nemoto, Kenji; Saito, Haruo; Ogawa, Yoshihiro; Takai, Yoshihiro; Yamada, Shogo

    2005-07-01

    Purpose: To evaluate the factors associated with acute esophagitis in lung cancer patients treated with thoracic radiotherapy. Methods and Materials: We examined 35 patients with non-small-cell lung cancer (n = 27, 77%) and small-cell lung cancer (n = 8, 23%) treated with thoracic radiotherapy between February 2003 and November 2004. The median patient age was 70 years (range, 50-83 years). The disease stage was Stage I in 2 patients (6%), Stage II in 1 (3%), Stage IIIa in 10 (28%), Stage IIIb in 9 (26%), and Stage IV in 9 (26%); 4 patients (11%) had recurrent disease after surgery. A median dose of 60 Gy (range, 50-67 Gy) was given to the isocenter and delivered in single daily fractions of 1.8 or 2 Gy. With heterogeneity corrections, the median given dose to the isocenter was 60.3 Gy (range, 49.9-67.2 Gy). Of the 35 patients, 30 (86%) received concurrent chemotherapy consisting of a platinum agent, cisplatin or carboplatin, combined with paclitaxel in 18 patients (52%), irinotecan hydrochloride in 7 (20%), vincristine sulfate and etoposide in 2 (5%), vinorelbine ditartrate in 1 (3%), etoposide in 1 (3%), and docetaxel in 1 patient (3%). Three of these patients underwent induction therapy with cisplatin and irinotecan hydrochloride, administered before thoracic radiotherapy, and concurrent chemotherapy. Esophageal toxicity was graded according to the Radiation Therapy Oncology Group criteria. The following factors were analyzed with respect to their association with Grade 1 or worse esophagitis by univariate and multivariate analyses: age, gender, concurrent chemotherapy, chemotherapeutic agents, maximal esophageal dose, mean esophageal dose, and percentage of esophageal volume receiving >10 to >65 Gy in 5-Gy increments. Results: Of the 35 patients, 25 (71%) developed acute esophagitis, with Grade 1 in 20 (57%) and Grade 2 in 5 (14%). None of the patients had Grade 3 or worse toxicity. The most significant correlation was between esophagitis and percentage of

  18. [Role of biomarkers in the differential diagnosis of acute respiratory failure in the immediate postoperative period of lung transplantation].

    PubMed

    Ruano, L; Sacanell, J; Roman, A; Rello, J

    2013-01-01

    Lung transplant recipients are at high risk of suffering many complications during the immediate postoperative period, such as primary graft dysfunction, acute graft rejection or infection. The most common symptom is the presence of acute respiratory failure, and the use of biomarkers could be useful for establishing an early diagnosis of these conditions. Different biomarkers have been studied, but none have proven to be the gold standard in the differential diagnosis of acute respiratory failure. This paper offers a review of the different biomarkers that have been studied in this field. PMID:23462428

  19. DO ACUTE PHASE PROTEINS REFLECT SEVERITY OF INFLAMMATION IN RAT MODELS OF POLLUTANT-INDUCED LUNG INJURY?

    EPA Science Inventory

    Title: DO ACUTE PHASE PROTEINS REFLECT THE SEVERITY OF INFLAMMATION IN RAT MODELS OF POLLUTANT-INDUCED LUNG INJURY?

    M. C. Schladweiler, BS 1, P. S. Gilmour, PhD 2, D. L. Andrews, BS 1, D. L. Costa, ScD 1, A. D. Ledbetter, BS 1, K. E. Pinkerton, PhD 3 and U. P. Kodavanti, ...

  20. Adenoviral augmentation of elafin protects the lung against acute injury mediated by activated neutrophils and bacterial infection.

    PubMed

    Simpson, A J; Wallace, W A; Marsden, M E; Govan, J R; Porteous, D J; Haslett, C; Sallenave, J M

    2001-08-01

    During acute pulmonary infection, tissue injury may be secondary to the effects of bacterial products or to the effects of the host inflammatory response. An attractive strategy for tissue protection in this setting would combine antimicrobial activity with inhibition of human neutrophil elastase (HNE), a key effector of neutrophil-mediated tissue injury. We postulated that genetic augmentation of elafin (an endogenous inhibitor of HNE with intrinsic antimicrobial activity) could protect the lung against acute inflammatory injury without detriment to host defense. A replication-deficient adenovirus encoding elafin cDNA significantly protected A549 cells against the injurious effects of both HNE and whole activated human neutrophils in vitro. Intratracheal replication-deficient adenovirus encoding elafin cDNA significantly protected murine lungs against injury mediated by Pseudomonas aeruginosa in vivo. Genetic augmentation of elafin therefore has the capacity to protect the lung against the injurious effects of both bacterial pathogens resistant to conventional antibiotics and activated neutrophils. PMID:11466403

  1. Effects and mechanism analysis of combined infusion by levosimendan and vasopressin on acute lung injury in rats septic shock.

    PubMed

    Wang, Xuebing; Ma, Shaolin; Liu, Yang; Xu, Wei; Li, Zhanxia

    2014-12-01

    This research is aimed to discover the influence and underling mechanism of combined infusion of arginine vasopressin with levosimendan on acute lung injury in rat septic shock with norepinephrine supplemented. The traditional fecal peritonitis-induced septic shock model was undergone in rats for study. It is observed that the combined infusion supplemented with norepinephrine brought about a lower mean pulmonary artery pressure; lower high-mobility group box 1 levels, pulmonary levels of interleukin-6, and arterial total nitrate/nitrite; lower apoptotic cells scores and total histological scores; but higher pulmonary gas exchange when compared with the separate infusion group and norepinephrine group. This therapy shows potential clinical beneficial assistance in sepsis-induced acute lung injury. The results suggest the mechanism of such effect is through abating pulmonary artery pressure, and more importantly suppressing inflammatory responses in lung when compared with norepinephrine infusion group and the separate infusion of levosimendan or vasopressin alone. PMID:25002345

  2. Altered Lipid Composition of Surfactant and Lung Tissue in Murine Experimental Malaria-Associated Acute Respiratory Distress Syndrome

    PubMed Central

    Scaccabarozzi, Diletta; Deroost, Katrien; Lays, Natacha; Taramelli, Donatella

    2015-01-01

    Malaria-associated acute lung injury (MA-ALI) and its more severe form malaria-associated acute respiratory distress syndrome (MA-ARDS) are common, often fatal complications of severe malaria infections. However, little is known about their pathogenesis. In this study, biochemical alterations of the lipid composition of the lungs were investigated as possible contributing factors to the severity of murine MA-ALI/ARDS. C57BL/6J mice were infected with Plasmodium berghei NK65 to induce lethal MA-ARDS, or with Plasmodium chabaudi AS, a parasite strain that does not induce lung pathology. The lipid profile of the lung tissue from mice infected with Plasmodium berghei NK65 developing MA-ALI/ARDS, but not that from mice without lung pathology or controls, was characterized by high levels of phospholipids -mainly phosphatidylcholine- and esterified cholesterol. The high levels of polyunsaturated fatty acids and the linoleic/oleic fatty acid ratio of the latter reflect the fatty acid composition of plasma cholesterol esters. In spite of the increased total polyunsaturated fatty acid pool, which augments the relative oxidability of the lung membranes, and the presence of hemozoin, a known pro-oxidant, no excess oxidative stress was detected in the lungs of Plasmodium berghei NK65 infected mice. The bronchoalveolar lavage (BAL) fluid of Plasmodium berghei NK65 infected mice was characterized by high levels of plasma proteins. The phospholipid profile of BAL large and small aggregate fractions was also different from uninfected controls, with a significant increase in the amounts of sphingomyelin and lysophosphatidylcholine and the decrease in phosphatidylglycerol. Both the increase of proteins and lysophosphatidylcholine are known to decrease the intrinsic surface activity of surfactant. Together, these data indicate that an altered lipid composition of lung tissue and BAL fluid, partially ascribed to oedema and lipoprotein infiltration, is a characteristic feature of murine

  3. Altered Lipid Composition of Surfactant and Lung Tissue in Murine Experimental Malaria-Associated Acute Respiratory Distress Syndrome.

    PubMed

    Scaccabarozzi, Diletta; Deroost, Katrien; Lays, Natacha; Omodeo Salè, Fausta; Van den Steen, Philippe E; Taramelli, Donatella

    2015-01-01

    Malaria-associated acute lung injury (MA-ALI) and its more severe form malaria-associated acute respiratory distress syndrome (MA-ARDS) are common, often fatal complications of severe malaria infections. However, little is known about their pathogenesis. In this study, biochemical alterations of the lipid composition of the lungs were investigated as possible contributing factors to the severity of murine MA-ALI/ARDS. C57BL/6J mice were infected with Plasmodium berghei NK65 to induce lethal MA-ARDS, or with Plasmodium chabaudi AS, a parasite strain that does not induce lung pathology. The lipid profile of the lung tissue from mice infected with Plasmodium berghei NK65 developing MA-ALI/ARDS, but not that from mice without lung pathology or controls, was characterized by high levels of phospholipids -mainly phosphatidylcholine- and esterified cholesterol. The high levels of polyunsaturated fatty acids and the linoleic/oleic fatty acid ratio of the latter reflect the fatty acid composition of plasma cholesterol esters. In spite of the increased total polyunsaturated fatty acid pool, which augments the relative oxidability of the lung membranes, and the presence of hemozoin, a known pro-oxidant, no excess oxidative stress was detected in the lungs of Plasmodium berghei NK65 infected mice. The bronchoalveolar lavage (BAL) fluid of Plasmodium berghei NK65 infected mice was characterized by high levels of plasma proteins. The phospholipid profile of BAL large and small aggregate fractions was also different from uninfected controls, with a significant increase in the amounts of sphingomyelin and lysophosphatidylcholine and the decrease in phosphatidylglycerol. Both the increase of proteins and lysophosphatidylcholine are known to decrease the intrinsic surface activity of surfactant. Together, these data indicate that an altered lipid composition of lung tissue and BAL fluid, partially ascribed to oedema and lipoprotein infiltration, is a characteristic feature of murine

  4. Effects of an endogenous nitric oxide synthase inhibitor on phorbol myristate acetate-induced acute lung injury in rats.

    PubMed

    Lin, Hen I; Chu, Shi Jye; Wang, David; Chen, Hsing I; Hsu, Kang

    2003-01-01

    1. In the present study, we determined whether the endogenous nitric oxide (NO) synthase (NOS) inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME) could ameliorate the acute lung injury (ALI) induced by phorbol myristate acetate (PMA) in rat isolated lung. 2. Typical ALI was induced successfully by PMA during 60 min of observation. At 2 micro g/kg, PMA elicited a significant increase in microvascular permeability (measured using the capillary filtration coefficient Kfc), lung weight gain, lung weight/bodyweight ratio, pulmonary arterial pressure (PAP) and protein concentration of bronchoalveolar lavage fluid. 3. Pretreatment with the NOS inhibitor l-NAME (5 mmol/L) significantly attenuated ALI. None of the parameters reflective of lung injury showed significant increase, except for PAP (P < 0.001). The addition of l-arginine (4 mmol/L) blocked the protective effective of l-NAME. Pretreatment with l-arginine exacerbated PMA-induced lung injury. 4. These data suggest that l-NAME significantly ameliorates ALI induced by PMA in rats, indicating that endogenous NO plays a key role in the development of lung oedema in PMA-induced lung injury. PMID:12859432

  5. [A Case of Acute Arterial Occlusion of the Lower Limb during Chemotherapy for Lung Cancer].

    PubMed

    Tanaka, Kentaro; Takada, Kazuto; Kojima, Eiji; Shimizu, Takahiro; Miyamatsu, Shohko; Nohara, Kango; Sakurai, Tsutomu; Mizuno, Takaaki; Yamashita, Yuuki

    2016-05-01

    A 69-year-old man visited a clinic for left leg weakness. With suspicions of lung cancer and a metastatic brain tumor, he was referred to our hospital and was diagnosed with large cell neuroendocrine carcinoma, cT1bN0M1b (BRA), stage IV. After stereotactic radiosurgery for his brain metastasis, he was treated with chemotherapy containing cisplatin and irinotecan. A week after initiating chemotherapy, he suddenly developed severe right leg pain and adynamia. A computed tomography angiogram revealed occlusion of the right common femoral artery, and percutaneous thrombectomy was performed. The symptoms resolved completely, and he was discharged without any sequelae or recurrence. Acute arterial occlusion of the limbs during chemotherapy is uncommon and requires prompt diagnosis and treatment; hence, caution should be paid when it is clinically suspected. PMID:27210093

  6. Adalimumab-induced acute interstitial lung disease in a patient with rheumatoid arthritis*

    PubMed Central

    Dias, Olívia Meira; Pereira, Daniel Antunes Silva; Baldi, Bruno Guedes; Costa, André Nathan; Athanazio, Rodrigo Abensur; Kairalla, Ronaldo Adib; Carvalho, Carlos Roberto Ribeiro

    2014-01-01

    The use of immunobiological agents for the treatment of autoimmune diseases is increasing in medical practice. Anti-TNF therapies have been increasingly used in refractory autoimmune diseases, especially rheumatoid arthritis, with promising results. However, the use of such therapies has been associated with an increased risk of developing other autoimmune diseases. In addition, the use of anti-TNF agents can cause pulmonary complications, such as reactivation of mycobacterial and fungal infections, as well as sarcoidosis and other interstitial lung diseases (ILDs). There is evidence of an association between ILD and the use of anti-TNF agents, etanercept and infliximab in particular. Adalimumab is the newest drug in this class, and some authors have suggested that its use might induce or exacerbate preexisting ILDs. In this study, we report the first case of acute ILD secondary to the use of adalimumab in Brazil, in a patient with rheumatoid arthritis and without a history of ILD. PMID:24626274

  7. Transfusion Related Acute Lung Injury after Cesarean Section in a Patient with HELLP Syndrome

    PubMed Central

    Moon, Kyoung Min; Rim, Ch'ang Bum; Kim, So Ri; Shin, Sang Ho; Kang, Min Seok; Lee, Jun Ho; Kim, Jihye; Kim, Sang Il

    2016-01-01

    Transfusion-related acute lung injury (TRALI) is a serious adverse reaction of transfusion, and presents as hypoxemia and non-cardiogenic pulmonary edema within 6 hours of transfusion. A 14-year-old primigravida woman at 34 weeks of gestation presented with upper abdominal pain without dyspnea. Because she showed the syndrome of HELLP (hemolysis, elevated liver enzymes, and low platelet count), an emergency cesarean section delivery was performed, and blood was transfused. In the case of such patients, clinicians should closely observe the patient's condition at least during the 6 hours while the patient receives blood transfusion, and should suspect TRALI if the patient complains of respiratory symptoms such as dyspnea. Furthermore, echocardiography should be performed to distinguish between the different types of transfusion-related adverse reactions. PMID:26885326

  8. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

    PubMed

    Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

    2015-12-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak. PMID:26432864

  9. Bedside Lung Ultrasound During Acute Chest Syndrome in Sickle Cell Disease

    PubMed Central

    Razazi, Keyvan; Deux, Jean-François; de Prost, Nicolas; Boissier, Florence; Cuquemelle, Elise; Galactéros, Frédéric; Rahmouni, Alain; Maître, Bernard; Brun-Buisson, Christian; Mekontso Dessap, Armand

    2016-01-01

    Abstract Lung ultrasound (LU) is increasingly used to assess pleural and lung disease in intensive care unit (ICU) and emergency unit at the bedside. We assessed the performance of bedside chest radiograph (CR) and LU during severe acute chest syndrome (ACS), using computed tomography (CT) as the reference standard. We prospectively explored 44 ACS episodes (in 41 patients) admitted to the medical ICU. Three imaging findings were evaluated (consolidation, ground-glass opacities, and pleural effusion). A score was used to quantify and compare loss of lung aeration with each technique and assess its association with outcome. A total number of 496, 507, and 519 lung regions could be assessed by CT scan, bedside CR, and bedside LU, respectively. Consolidations were the most common pattern and prevailed in lung bases (especially postero-inferior regions). The agreement with CT scan patterns was significantly higher for LU as compared to CR (κ coefficients of 0.45 ± 0.03 vs 0.30 ± 0.03, P < 0.01 for the parenchyma, and 0.73 ± 0.08 vs 0.06 ± 0.09, P < 0.001 for pleural effusion). The Bland and Altman analysis showed a nonfixed bias of −1.0 (P = 0.12) between LU score and CT score whereas CR score underestimated CT score with a fixed bias of −5.8 (P < 0.001). The specificity for the detection of consolidated regions or pleural effusion (using CT scan as the reference standard) was high for LU and CR, whereas the sensitivity was high for LU but low for CR. As compared to others, ACS patients with an LU score above the median value of 11 had a larger volume of transfused and exsanguinated blood, greater oxygen requirements, more need for mechanical ventilation, and a longer ICU length of stay. LU outperformed CR for the diagnosis of consolidations and pleural effusion during ACS. Higher values of LU score identified patients at risk of worse outcome. PMID:26886600

  10. Mechanisms of decreased intestinal epithelial proliferation and increased apoptosis in murine acute lung injury

    PubMed Central

    Husain, Kareem D.; Stromberg, Paul E.; Woolsey, Cheryl A.; Turnbull, Isaiah R.; Dunne, W. Michael; Javadi, Pardis; Buchman, Timothy G.; Karl, Irene E.; Hotchkiss, Richard S.; Coopersmith, Craig M.

    2005-01-01

    Objectives The aim of this study was to determine the effects of acute lung injury (ALI) on the gut epithelium and examine mechanisms underlying changes in crypt proliferation and apoptosis. The relationship between severity and timing of lung injury to intestinal pathology was also examined. Design Randomized, controlled study. Setting University research laboratory. Subjects Genetically inbred mice. Interventions Following induction of ALI, gut epithelial proliferation and apoptosis was assessed in a) C3H/HeN wild type and C3H/HeJ mice, that lack functional toll-like receptor 4 (TLR4, n=17), b) C57Bl/6 mice that received monoclonal anti-tumor necrosis factor-α (TNFα) or control antibody (n=22) and c) C57Bl/6 wild type and transgenic mice that overexpress Bcl-2 in their gut epithelium (n=21). Intestinal epithelial proliferation and death were also examined in animals with differing degrees of lung inflammation (n=24) as well as in a timecourse analysis following a fixed injury (n=18). Measurements and Main Results ALI caused decreased proliferation and increased apoptosis in crypt epithelial cells in all animals studied. C3H/HeJ mice had higher levels of proliferation than C3H/HeN animals without additional changes in apoptosis. Anti-TNFα antibody had no effect on gut epithelial proliferation or death. Overexpression of Bcl-2 did not change proliferation despite decreasing gut apoptosis. Proliferation and apoptosis were not correlated to severity of lung injury, as gut alterations were lost in mice with more severe ALI. Changes in both gut epithelial proliferation and death were apparent within 12 hours, but proliferation was decreased 36 hours following ALI while apoptosis returned to normal. Conclusions ALI causes disparate effects on crypt proliferation and apoptosis, which occur, at least in part, through differing mechanisms involving TLR4 and Bcl-2. Severity of lung injury does not correlate with perturbations in proliferation or death in the gut

  11. Acute Lung Injury Complicating Blood Transfusion in Post-Partum Hemorrhage: Incidence and Risk Factors

    PubMed Central

    Teofili, Luciana; Bianchi, Maria; Zanfini, Bruno A.; Catarci, Stefano; Sicuranza, Rossella; Spartano, Serena; Zini, Gina; Draisci, Gaetano

    2014-01-01

    Background We retrospectively investigated the incidence and risk factors for transfusion-related acute lung injury (TRALI) among patients transfused for post-partum hemorrhage (PPH). Methods We identified a series of 71 consecutive patients with PPH requiring the urgent transfusion of three or more red blood cell (RBC) units, with or without transfusion of fresh frozen plasma (FFP) and/or platelets (PLT). Clinical records were then retrieved and examined for respiratory distress events. According to the 2004 consensus definition, cases of new-onset hypoxemia, within 6 hours after transfusion, with bilateral pulmonary changes, in the absence of cardiogenic pulmonary edema were identified as TRALI. If an alternative risk factor for acute lung injury was present, possible TRALI was diagnosed. Results Thirteen cases of TRALI and 1 case of possible TRALI were identified (overall incidence 19.7%). At univariate analysis, patients with TRALI received higher number of RBC, PLT and FFP units and had a longer postpartum hospitalization. Among the diseases occurring in pregnancy- and various pre-existing comorbidities, only gestational hypertension and pre-eclampsia, significantly increased the risk to develop TRALI (p = 0.006). At multivariate analysis including both transfusion- and patient-related risk factors, pregnancy-related, hypertensive disorders were confirmed to be the only predictors for TRALI, with an odds ratio of 27.7 ( 95% CI 1.27–604.3, p=0.034). Conclusions Patients suffering from PPH represent a high-risk population for TRALI. The patients with gestational hypertension and pre-eclampsia, not receiving anti-hypertensive therapy, have the highest risk. Therefore, a careful monitoring of these patients after transfusions is recommended. PMID:25408855

  12. β1-Na(+),K(+)-ATPase gene therapy upregulates tight junctions to rescue lipopolysaccharide-induced acute lung injury.

    PubMed

    Lin, X; Barravecchia, M; Kothari, P; Young, J L; Dean, D A

    2016-06-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with diverse disorders and characterized by disruption of the alveolar-capillary barrier, leakage of edema fluid into the lung, and substantial inflammation leading to acute respiratory failure. Gene therapy is a potentially powerful approach to treat ALI/ARDS through repair of alveolar epithelial function. Herein, we show that delivery of a plasmid expressing β1-subunit of the Na(+),K(+)-ATPase (β1-Na(+),K(+)-ATPase) alone or in combination with epithelial sodium channel (ENaC) α1-subunit using electroporation not only protected from subsequent lipopolysaccharide (LPS)-mediated lung injury, but also treated injured lungs. However, transfer of α1-subunit of ENaC (α1-ENaC) alone only provided protection benefit rather than treatment benefit although alveolar fluid clearance had been remarkably enhanced. Gene transfer of β1-Na(+),K(+)-ATPase, but not α1-ENaC, not only enhanced expression of tight junction protein zona occludins-1 (ZO-1) and occludin both in cultured cells and in mouse lungs, but also reduced pre-existing increase of lung permeability in vivo. These results demonstrate that gene transfer of β1-Na(+),K(+)-ATPase upregulates tight junction formation and therefore treats lungs with existing injury, whereas delivery of α1-ENaC only maintains pre-existing tight junction but not for generation. This indicates that the restoration of epithelial/endothelial barrier function may provide better treatment of ALI/ARDS. PMID:26910760

  13. Non–Muscle Myosin Light Chain Kinase Isoform Is a Viable Molecular Target in Acute Inflammatory Lung Injury

    PubMed Central

    Mirzapoiazova, Tamara; Moitra, Jaideep; Moreno-Vinasco, Liliana; Sammani, Saad; Turner, Jerry R.; Chiang, Eddie T.; Evenoski, Carrie; Wang, Ting; Singleton, Patrick A.; Huang, Yong; Lussier, Yves A.; Watterson, D. Martin; Dudek, Steven M.; Garcia, Joe G. N.

    2011-01-01

    Acute lung injury (ALI) and mechanical ventilator-induced lung injury (VILI), major causes of acute respiratory failure with elevated morbidity and mortality, are characterized by significant pulmonary inflammation and alveolar/vascular barrier dysfunction. Previous studies highlighted the role of the non–muscle myosin light chain kinase isoform (nmMLCK) as an essential element of the inflammatory response, with variants in the MYLK gene that contribute to ALI susceptibility. To define nmMLCK involvement further in acute inflammatory syndromes, we used two murine models of inflammatory lung injury, induced by either an intratracheal administration of lipopolysaccharide (LPS model) or mechanical ventilation with increased tidal volumes (the VILI model). Intravenous delivery of the membrane-permeant MLC kinase peptide inhibitor, PIK, produced a dose-dependent attenuation of both LPS-induced lung inflammation and VILI (∼50% reductions in alveolar/vascular permeability and leukocyte influx). Intravenous injections of nmMLCK silencing RNA, either directly or as cargo within angiotensin-converting enzyme (ACE) antibody–conjugated liposomes (to target the pulmonary vasculature selectively), decreased nmMLCK lung expression (∼70% reduction) and significantly attenuated LPS-induced and VILI-induced lung inflammation (∼40% reduction in bronchoalveolar lavage protein). Compared with wild-type mice, nmMLCK knockout mice were significantly protected from VILI, with significant reductions in VILI-induced gene expression in biological pathways such as nrf2-mediated oxidative stress, coagulation, p53-signaling, leukocyte extravasation, and IL-6–signaling. These studies validate nmMLCK as an attractive target for ameliorating the adverse effects of dysregulated lung inflammation. PMID:20139351

  14. Acute Abdominal Pain after Intercourse: Adrenal Hemorrhage as the First Sign of Metastatic Lung Cancer

    PubMed Central

    Packer, Clifford D.

    2014-01-01

    Although the adrenal glands are a common site of cancer metastases, they are often asymptomatic and discovered incidentally on CT scan or autopsy. Spontaneous adrenal hemorrhage associated with metastatic lung cancer is an exceedingly rare phenomenon, and diagnosis can be difficult due to its nonspecific symptoms and ability to mimic other intra-abdominal pathologies. We report a case of a 65-year-old man with a history of right upper lobectomy seven months earlier for stage IB non-small cell lung cancer who presented with acute abdominal pain after intercourse. CT scan revealed a new right adrenal mass with surrounding hemorrhage, and subsequent FDG-PET scan confirmed new metabolic adrenal metastases. The patient's presentation of abdominal pain and adrenal hemorrhage immediately after sexual intercourse suggests that exertion, straining, or increased intra-abdominal pressure might be risk factors for precipitation of hemorrhage in patients with adrenal metastases. Management includes pain control and supportive treatment in mild cases, with arterial embolization or adrenalectomy being reserved for cases of severe hemorrhage. PMID:25126096

  15. Increased extravascular lung water reduces the efficacy of alveolar recruitment maneuver in acute respiratory distress syndrome.

    PubMed

    Smetkin, Alexey A; Kuzkov, Vsevolod V; Suborov, Eugeny V; Bjertnaes, Lars J; Kirov, Mikhail Y

    2012-01-01

    Introduction. In acute respiratory distress syndrome (ARDS) the recruitment maneuver (RM) is used to reexpand atelectatic areas of the lungs aiming to improve arterial oxygenation. The goal of our paper was to evaluate the response to RM, as assessed by measurements of extravascular lung water index (EVLWI) in ARDS patients. Materials and Methods. Seventeen adult ARDS patients were enrolled into a prospective study. Patients received protective ventilation. The RM was performed by applying a continuous positive airway pressure of 40 cm H(2)O for 40 sec. The efficacy of the RM was assessed 5 min later. Patients were identified as responders if PaO(2)/FiO(2) increased by >20% above the baseline. EVLWI was assessed by transpulmonary thermodilution before the RM, and patients were divided into groups of low EVLWI (<10 mL/kg) and high EVLWI (≥10 mL/kg). Results. EVLWI was increased in 12 patients. Following RM, PaO(2)/FiO(2) increased by 33 (4-65) % in the patients with low EVLWI, whereas those in the high EVLWI group experienced a change by only -1((-13)-(+5)) % (P = 0.035). Conclusion. In ARDS, the response to a recruitment maneuver might be related to the severity of pulmonary edema. In patients with incresed EVLWI, the recruitment maneuver is less effective. PMID:22649717

  16. Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H.

    PubMed

    Xiao, Qiang; Dong, Ningning; Yao, Xue; Wu, Dang; Lu, Yanli; Mao, Fei; Zhu, Jin; Li, Jian; Huang, Jin; Chen, Aifang; Huang, Lu; Wang, Xuehai; Yang, Guangxiao; He, Guangyuan; Xu, Yong; Lu, Weiqiang

    2016-01-01

    Neutrophils play an important role in the occurrence and development of acute lung injury (ALI). Leukotriene B4 (LTB4), a hydrolysis product of epoxide leukotriene A4 (LTA4) catalyzed by LTA4 hydrolase (LTA4H), is one of the most potent chemoattractants for neutrophil. Bufexamac is a drug widely used as an anti-inflammatory agent on the skin, however, the mechanism of action is still not fully understood. In this study, we found bufexamac was capable of specifically inhibiting LTA4H enzymatic activity and revealed the mode of interaction of bufexamac and LTA4H using X-ray crystallography. Moreover, bufexamac significantly prevented the production of LTB4 in neutrophil and inhibited the fMLP-induced neutrophil migration through inhibition of LTA4H. Finally, bufexamac significantly attenuated lung inflammation as reflected by reduced LTB4 levels and weakened neutrophil infiltration in bronchoalveolar lavage fluid from a lipopolysaccharide-induced ALI mouse model. In summary, our study indicates that bufexamac acts as an inhibitor of LTB4 biosynthesis and may have potential clinical applications for the treatment of ALI. PMID:27126280

  17. Tenuigenin ameliorates acute lung injury by inhibiting NF-κB and MAPK signalling pathways.

    PubMed

    Lv, Hongming; Zhu, Chao; Liao, Yuanjun; Gao, Yawen; Lu, Gejin; Zhong, Weiting; Zheng, Yuwei; Chen, Wei; Ci, Xinxin

    2015-09-15

    We aimed to explore the protective effect of tenuigenin (TNG) on lipopolysaccharide (LPS)-stimulated inflammatory responses in acute lung injury (ALI). Thus, we assessed the effects of TNG on the LPS-induced production of tumour necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the culture supernatants of RAW 264.7 cells. Male BALB/c mice were pretreated with commercial TNG (2, 4 and 8 mg/kg) and dexamethasone (Dex, 5mg/kg) for 1h prior to LPS (0.5 mg/kg) challenge. After 12h, airway inflammation was assessed. Our results showed that TNG dramatically decreased the production of TNF-α, IL-1β, and IL-6 in vitro and in vivo as well as the expression of COX-2 protein in vivo. Treatment with TNG not only significantly ameliorated LPS-stimulated histopathological changes but also reduced the myeloperoxidase (MPO) activity and the wet-to-dry weight ratio of the lungs. Furthermore, TNG blocked IκBα phosphorylation and degradation and inhibited p38/ERK phosphorylation in LPS-induced ALI. These findings suggest that TNG may have a protective effect on LPS-induced ALI and may be useful for the prevention and treatment of ALI in the clinical setting. PMID:25930113

  18. Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H

    PubMed Central

    Xiao, Qiang; Dong, Ningning; Yao, Xue; Wu, Dang; Lu, Yanli; Mao, Fei; Zhu, Jin; Li, Jian; Huang, Jin; Chen, Aifang; Huang, Lu; Wang, Xuehai; Yang, Guangxiao; He, Guangyuan; Xu, Yong; Lu, Weiqiang

    2016-01-01

    Neutrophils play an important role in the occurrence and development of acute lung injury (ALI). Leukotriene B4 (LTB4), a hydrolysis product of epoxide leukotriene A4 (LTA4) catalyzed by LTA4 hydrolase (LTA4H), is one of the most potent chemoattractants for neutrophil. Bufexamac is a drug widely used as an anti-inflammatory agent on the skin, however, the mechanism of action is still not fully understood. In this study, we found bufexamac was capable of specifically inhibiting LTA4H enzymatic activity and revealed the mode of interaction of bufexamac and LTA4H using X-ray crystallography. Moreover, bufexamac significantly prevented the production of LTB4 in neutrophil and inhibited the fMLP-induced neutrophil migration through inhibition of LTA4H. Finally, bufexamac significantly attenuated lung inflammation as reflected by reduced LTB4 levels and weakened neutrophil infiltration in bronchoalveolar lavage fluid from a lipopolysaccharide-induced ALI mouse model. In summary, our study indicates that bufexamac acts as an inhibitor of LTB4 biosynthesis and may have potential clinical applications for the treatment of ALI. PMID:27126280

  19. Higher Risk of Acute Cellular Rejection in Lung Transplant Recipients with Cystic Fibrosis.

    PubMed

    Calabrese, Fiorella; Lunardi, Francesca; Nannini, Nazarena; Balestro, Elisabetta; Loy, Monica; Marulli, Giuseppe; Calabrese, Francesca; Vuljan, Stefania Edith; Schiavon, Marco; Perissinotto, Egle; Rea, Federico

    2015-01-01

    BACKGROUND Acute cellular rejection (ACR) affects up to 40% of recipients within the first year after lung transplant (LTx). The aim of this study was to determine the frequency of ACR and associated major risk factors in cystic fibrosis (CF) recipients. Bronchiolitis obliterans syndrome (BOS) and 1-year/long-term survival were also evaluated. MATERIAL AND METHODS ACR was reviewed in 643 scheduled biopsies from 44 CF (Group 1) versus 89 other recipients (Group 2). We performed univariate/multivariate analyses of risk factors for ACR and BOS, and survival analysis. RESULTS Group 1 showed higher ACR frequency, especially for ACR ≥ A2. Multivariable generalized linear models considering both native lung disease and age showed that higher values of ACR index were significantly related to the pretransplant diagnosis of CF. BOS and long-term survival were not influenced by the increased incidence of ACR. Poorer long-term survival was observed in Group 2. CONCLUSIONS CF recipients have a higher ACR risk, which may be due to enhanced immune activation related to a genetic disorder, and younger age. PMID:26718747

  20. Protective effect of abamectin on acute lung injury induced by lipopolysaccharide in mice.

    PubMed

    Zhang, Xiaozhe; Li, Jianhua; Chen, Chi; Ci, Xinxin; Yu, Qinlei; Zhang, Xichen; Deng, Xuming

    2011-12-01

    Abamectin, a broad-spectrum antiparasitic agent, has been shown to exert an anti-inflammatory effect, in vitro, by down regulating both the nuclear transcription factor kappa-B and the mitogen-activated protein kinase (MAPK) activation pathway. In this study, we investigated the role of abamectin in acute lung injury (ALI) induced by Lipopolysaccharide (LPS), and the invovment of MAPK and NF-κB. BALB/C mice were administered abamectin (PBS) orally, followed by a dose of 0.5 mg/kg of LPS. After 10 h, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) were measured using enzyme-linked immunosorbent assay. The number of total cells, neutrophils, and macrophages in the BALF were determined. The right lung was then excised for histological examination and analysis of myeloperoxidase (MPO) activity. Phosphorylation of MAPK family and IκB were detected by western blot. We found that 2 mg/kg of abamectin had significant protective effects on ALI. Mice treated with LPS alone showed markedly increased TNF-α and IL-6 levels in the BALF. In addition, not only was the W/D ratio of lung tissue significantly decreased, the number of total cells, neutrophils and macrophages in the BALF was also significantly reduced 11 h after treatment with abamectin. Furthermore, p38MAPK, ERK, and IκB were activated in 10 h after LPS treatment, which could be blunted by Abamectin. These results indicate that abamectin could attenuate inflammatory injury induced by LPS through MAPK and NF-κB passway. PMID:21118302

  1. Erythropoietin Pretreatment Attenuates Seawater Aspiration-Induced Acute Lung Injury in Rats.

    PubMed

    Ji, Mu-huo; Tong, Jian-hua; Tan, Yuan-hui; Cao, Zhen-yu; Ou, Cong-yang; Li, Wei-yan; Yang, Jian-jun; Peng, Y G; Zhu, Si-hai

    2016-02-01

    Seawater drowning-induced acute lung injury (ALI) is a serious clinical condition characterized by increased alveolar-capillary permeability, excessive inflammatory responses, and refractory hypoxemia. However, current therapeutic options are largely supportive; thus, it is of great interest to search for alternative agents to treat seawater aspiration-induced ALI. Erythropoietin (EPO) is a multifunctional agent with antiinflammatory, antioxidative, and antiapoptotic properties. However, the effects of EPO on seawater aspiration-induced ALI remain unclear. In the present study, male rats were randomly assigned to the naive group, normal saline group, seawater group, or seawater + EPO group. EPO was administered intraperitoneally at 48 and 24 h before seawater aspiration. Arterial blood gas analysis was performed with a gas analyzer at baseline, 30 min, 1 h, 4 h, and 24 h after seawater aspiration, respectively. Histological scores, computed tomography scan, nuclear factor kappa B p65, inducible nitric oxide synthase, caspase-3, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-10, wet-to-dry weight ratio, myeloperoxidase activity, malondialdehyde, and superoxide dismutase in the lung were determined 30 min after seawater aspiration. Our results showed that EPO pretreatment alleviated seawater aspiration-induced ALI, as indicated by increased arterial partial oxygen tension and decreased lung histological scores. Furthermore, EPO pretreatment attenuated seawater aspiration-induced increase in the expressions of pulmonary nuclear factor kappa B p65, inducible nitric oxide synthase, caspase-3, tumor necrosis factor-alpha, IL-1β, myeloperoxidase activity, and malondialdehyde when compared with the seawater group. Collectively, our study suggested that EPO pretreatment attenuates seawater aspiration-induced ALI by down-regulation of pulmonary pro-inflammatory cytokines, oxidative stress, and apoptosis. PMID:26454446

  2. Galantamine protects against lipopolysaccharide-induced acute lung injury in rats.

    PubMed

    Li, G; Zhou, C L; Zhou, Q S; Zou, H D

    2016-02-01

    Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats. PMID:26648090

  3. Mast cells modulate acute ozone-induced inflammation of the murine lung

    SciTech Connect

    Kleeberger, S.R.; Seiden, J.E.; Levitt, R.C.; Zhang, L.Y. )

    1993-11-01

    We hypothesized that mast cells modulate lung inflammation that develops after acute ozone (O3) exposure. Two tests were done: (1) genetically mast-cell-deficient (WBB6F1-W/Wv, WCB6F1-SI/SId) and bone-marrow-transplanted W/Wv mice were exposed to O3 or filtered air, and the inflammatory responses were compared with those of mast-cell-sufficient congenic mice (WBB6F1-(+)/+, WCB6F1-(+)/+); (2) genetically O3-susceptible C57BL/6J mice were treated pharmacologically with putative mast-cell modulators or vehicle, and the O3-induced inflammatory responses were compared. Mice were exposed to 1.75 ppm O3 or air for 3 h, and lung inflammation was assessed by bronchoalveolar lavage (BAL) 6 and 24 h after exposure. Relative to O3-exposed W/Wv and SI/SId mice, the mean numbers of lavageable polymorphonuclear leukocytes (PMNs) and total BAL protein concentration (a marker of permeability) were significantly greater in the respective O3-exposed normal congenic +/+ mice (p < 0.05). Mast cells were reconstituted in W/Wv mice by transplantation of bone marrow cells from congenic +/+ mice, and O3-induced lung inflammation was assessed in the mast-cell-replete W/Wv mice. After O3 exposure, the changes in lavageable PMNs and total protein of mast-cell-replete W/Wv mice were not different from age-matched normal +/+ control mice, and they were significantly greater than those of sham-transplanted W/Wv mice (p < 0.05). Genetically susceptible C57BL/6J mice were pretreated with a mast-cell stabilizer (nedocromil sodium), secretagogue (compound 48/80), or vehicle, and the mice were exposed to O3.

  4. Galantamine protects against lipopolysaccharide-induced acute lung injury in rats

    PubMed Central

    Li, G.; Zhou, CL.; Zhou, QS.; Zou, HD.

    2015-01-01

    Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats. PMID:26648090

  5. CO2 elimination at varying inspiratory pause in acute lung injury.

    PubMed

    Aboab, J; Niklason, L; Uttman, L; Kouatchet, A; Brochard, L; Jonson, B

    2007-01-01

    Previous studies have indicated that, during mechanical ventilation, an inspiratory pause enhances gas exchange. This has been attributed to prolonged time during which fresh gas of the tidal volume is present in the respiratory zone and is available for distribution in the lung periphery. The mean distribution time of inspired gas (MDT) is the mean time during which fractions of fresh gas are present in the respiratory zone. All ventilators allow setting of pause time, T(P), which is a determinant of MDT. The objective of the present study was to test in patients the hypothesis that the volume of CO(2) eliminated per breath, V(T)CO(2), is correlated to the logarithm of MDT as previously found in animal models. Eleven patients with acute lung injury were studied. When T(P) increased from 0% to 30%, MDT increased fourfold. A change of T(P) from 10% to 0% reduced V(T)CO(2) by 14%, while a change to 30% increased V(T)CO(2) by 19%. The relationship between V(T)CO(2) and MDT was in accordance with the logarithmic hypothesis. The change in V(T)CO(2) reflected to equal extent changes in airway dead space and alveolar PCO(2) read from the alveolar plateau of the single breath test for CO(2). By varying T(P), effects are observed on V(T)CO(2), airway dead space and alveolar PCO(2). These effects depend on perfusion, gas distribution and diffusion in the lung periphery, which need to be further elucidated. PMID:17204030

  6. Cellular kinetics in the lungs of aging Fischer 344 rats after acute exposure to ozone.

    PubMed Central

    Vincent, R.; Adamson, I. Y.

    1995-01-01

    Lung repair in aging Fischer 344 male rats was investigated after an acute inhalation exposure to ozone. Adult (9-month-old) and senescent (24-month-old) rats were exposed to 0.8 ppm ozone for a single period of 6 hours, and thereafter studied over 5 days of recovery in clean air. The animals were given intraperitoneal injections of colchicine and [3H]thymidine, 4 hours and 1.5 hours before termination, respectively. The lungs were inflated with glutaraldehyde, and tissue samples were embedded in epoxy resin for electron microscopy, or in glycol methacrylate for light-microscopic autoradiography. Exposure to ozone produced epithelial injury in alveolar ducts and terminal bronchioles, later reflected by the transient increase in mitotic activity of nonciliated bronchiolar cells and alveolar type 2 cells. The increase in metaphase-arrested cells and [3H]thymidine-labeled cells in bronchioles followed similar time courses, ie, maximal at days 1.5 to 2, and subsiding by day 3. In the alveoli, type 1 cell necrosis was observed early after exposure (6 hours recovery), without notable structural changes in the interstitial and endothelial compartments. The increased mitotic activity in the alveolar septa was mostly due to proliferation of epithelial type 2 cells, which was maximal at day 1.5, and of interstitial cells, maximal at day 2.5. The magnitude of the mitotic responses of nonciliated bronchiolar cells, alveolar type 2 cells and interstitial cells was highest (+50%) in the lungs of senescent rats. Although the cellular events during repair are essentially similar in both age groups, the results indicate that senescent rats have a significantly higher level of initial injury from inhalation of ozone than adult animals. Images Figure 1 Figure 2 Figure 5 PMID:7717445

  7. Proteomic Analysis of Lung Tissue in a Rat Acute Lung Injury Model: Identification of PRDX1 as a Promoter of Inflammation

    PubMed Central

    Liu, Dongdong; Mao, Pu; Huang, Yongbo; Liu, Yiting; Liu, Xiaoqing; Pang, Xiaoqing; Li, Yimin

    2014-01-01

    Acute respiratory distress syndrome (ARDS) remains a high morbidity and mortality disease entity in critically ill patients, despite decades of numerous investigations into its pathogenesis. To obtain global protein expression changes in acute lung injury (ALI) lung tissues, we employed a high-throughput proteomics method to identify key components which may be involved in the pathogenesis of ALI. In the present study, we analyzed lung tissue proteomes of Pseudomonas aeruginosa-induced ALI rats and identified eighteen proteins whose expression levels changed more than twofold as compared to normal controls. In particular, we found that PRDX1 expression in culture medium was elevated by a lipopolysaccharide (LPS) challenge in airway epithelial cells in vitro. Furthermore, overexpression of PRDX1 increased the expression of proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α), whereas knockdown of PRDX1 led to downregulated expression of cytokines induced by LPS. In conclusion, our findings provide a global alteration in the proteome of lung tissues in the ALI rat model and indicate that PRDX1 may play a critical role in the pathogenesis of ARDS by promoting inflammation and represent a novel strategy for the development of new therapies against ALI. PMID:25024510

  8. Acute Respiratory Failure in Critically Ill Patients with Interstitial Lung Disease

    PubMed Central

    Zafrani, Lara; Lemiale, Virginie; Lapidus, Nathanael; Lorillon, Gwenael; Schlemmer, Benoît; Azoulay, Elie

    2014-01-01

    Background Patients with chronic known or unknown interstitial lung disease (ILD) may present with severe respiratory flares that require intensive management. Outcome data in these patients are scarce. Patients and Methods Clinical and radiological features were collected in 83 patients with ILD-associated acute respiratory failure (ARF). Determinants of hospital mortality and response to corticosteroid therapy were identified by logistic regression. Results Hospital and 1-year mortality rates were 41% and 54% respectively. Pulmonary hypertension, computed tomography (CT) fibrosis and acute kidney injury were independently associated with mortality (odds ratio (OR) 4.55; 95% confidence interval (95%CI) (1.20–17.33); OR, 7.68; (1.78–33.22) and OR 10.60; (2.25–49.97) respectively). Response to steroids was higher in patients with shorter time from hospital admission to corticosteroid therapy. Patients with fibrosis on CT had lower response to steroids (OR, 0.03; (0.005–0.21)). In mechanically ventilated patients, overdistension induced by high PEEP settings was associated with CT fibrosis and hospital mortality. Conclusion Mortality is high in ILD-associated ARF. CT and echocardiography are valuable prognostic tools. Prompt corticosteroid therapy may improve survival. PMID:25115557

  9. Accuracy of Nurse-Performed Lung Ultrasound in Patients With Acute Dyspnea

    PubMed Central

    Mumoli, Nicola; Vitale, Josè; Giorgi-Pierfranceschi, Matteo; Cresci, Alessandra; Cei, Marco; Basile, Valentina; Brondi, Barbara; Russo, Elisa; Giuntini, Lucia; Masi, Lorenzo; Cocciolo, Massimo; Dentali, Francesco

    2016-01-01

    Abstract In clinical practice lung ultrasound (LUS) is becoming an easy and reliable noninvasive tool for the evaluation of dyspnea. The aim of this study was to assess the accuracy of nurse-performed LUS, in particular, in the diagnosis of acute cardiogenic pulmonary congestion. We prospectively evaluated all the consecutive patients admitted for dyspnea in our Medicine Department between April and July 2014. At admission, serum brain natriuretic peptide (BNP) levels and LUS was performed by trained nurses blinded to clinical and laboratory data. The accuracy of nurse-performed LUS alone and combined with BNP for the diagnosis of acute cardiogenic dyspnea was calculated. Two hundred twenty-six patients (41.6% men, mean age 78.7 ± 12.7 years) were included in the study. Nurse-performed LUS alone had a sensitivity of 95.3% (95% CI: 92.6–98.1%), a specificity of 88.2% (95% CI: 84.0–92.4%), a positive predictive value of 87.9% (95% CI: 83.7–92.2%) and a negative predictive value of 95.5% (95% CI: 92.7–98.2%). The combination of nurse-performed LUS with BNP level (cut-off 400 pg/mL) resulted in a higher sensitivity (98.9%, 95% CI: 97.4–100%), negative predictive value (98.8%, 95% CI: 97.2–100%), and corresponding negative likelihood ratio (0.01, 95% CI: 0.0, 0.07). Nurse-performed LUS had a good accuracy in the diagnosis of acute cardiogenic dyspnea. Use of this technique in combination with BNP seems to be useful in ruling out cardiogenic dyspnea. Other studies are warranted to confirm our preliminary findings and to establish the role of this tool in other settings. PMID:26945396

  10. Accuracy of Nurse-Performed Lung Ultrasound in Patients With Acute Dyspnea: A Prospective Observational Study.

    PubMed

    Mumoli, Nicola; Vitale, Josè; Giorgi-Pierfranceschi, Matteo; Cresci, Alessandra; Cei, Marco; Basile, Valentina; Brondi, Barbara; Russo, Elisa; Giuntini, Lucia; Masi, Lorenzo; Cocciolo, Massimo; Dentali, Francesco

    2016-03-01

    In clinical practice lung ultrasound (LUS) is becoming an easy and reliable noninvasive tool for the evaluation of dyspnea. The aim of this study was to assess the accuracy of nurse-performed LUS, in particular, in the diagnosis of acute cardiogenic pulmonary congestion. We prospectively evaluated all the consecutive patients admitted for dyspnea in our Medicine Department between April and July 2014. At admission, serum brain natriuretic peptide (BNP) levels and LUS was performed by trained nurses blinded to clinical and laboratory data. The accuracy of nurse-performed LUS alone and combined with BNP for the diagnosis of acute cardiogenic dyspnea was calculated. Two hundred twenty-six patients (41.6% men, mean age 78.7 ± 12.7 years) were included in the study. Nurse-performed LUS alone had a sensitivity of 95.3% (95% CI: 92.6-98.1%), a specificity of 88.2% (95% CI: 84.0-92.4%), a positive predictive value of 87.9% (95% CI: 83.7-92.2%) and a negative predictive value of 95.5% (95% CI: 92.7-98.2%). The combination of nurse-performed LUS with BNP level (cut-off 400 pg/mL) resulted in a higher sensitivity (98.9%, 95% CI: 97.4-100%), negative predictive value (98.8%, 95% CI: 97.2-100%), and corresponding negative likelihood ratio (0.01, 95% CI: 0.0, 0.07). Nurse-performed LUS had a good accuracy in the diagnosis of acute cardiogenic dyspnea. Use of this technique in combination with BNP seems to be useful in ruling out cardiogenic dyspnea. Other studies are warranted to confirm our preliminary findings and to establish the role of this tool in other settings. PMID:26945396

  11. Sex-specific differences in hyperoxic lung injury in mice: Implications for acute and chronic lung disease in humans

    SciTech Connect

    Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua; Couroucli, Xanthi I.; Barrios, Roberto; Moorthy, Bhagavatula

    2013-10-15

    Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO{sub 2} > 0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F{sub 2} alpha (8-iso-PGF 2α) (LC–MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F > M) and VEGF (M > F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans. - Highlights: • Male mice were more susceptible to hyperoxic lung injury than females. • Sex differences in inflammatory markers were observed. • CYP1A expression was higher in females after hyperoxia exposure.

  12. A Coin-Like Peripheral Small Cell Lung Carcinoma Associated with Acute Paraneoplastic Axonal Guillain-Barre-Like Syndrome

    PubMed Central

    Jung, Ioan; Gurzu, Simona; Balasa, Rodica; Motataianu, Anca; Contac, Anca Otilia; Halmaciu, Ioana; Popescu, Septimiu; Simu, Iunius

    2015-01-01

    Abstract A 65-year-old previously healthy male heavy smoker was hospitalized with a 2-week history of progressive muscle weakness in the lower and upper extremities. After 10 days of hospitalization, urinary sphincter incompetence and fecal incontinence were added and tetraparesis was established. The computer-tomography scan examination revealed a massive right hydrothorax and multifocal solid acinar structures with peripheral localization in the left lung, which suggested pulmonary cancer. Bone marrow metastases were also suspected. Based on the examination results, the final diagnosis was acute paraneoplastic axonal Guillain-Barre-like syndrome. The patient died 3 weeks after hospitalization. At autopsy, bronchopneumonia and a right hydrothorax were confirmed. Several 4 to 5-mm-sized round peripherally located white nodules were identified in the left lung, without any central tumor mass. Under microscope, a coin-shaped peripheral/subpleural small cell carcinoma was diagnosed, with generalized bone metastases. A huge thrombus in the abdominal aorta and acute pancreatitis was also seen at autopsy. This case highlights the difficulty of diagnosis of lung carcinomas and the necessity of a complex differential diagnosis of severe progressive ascending neuropathies. This is the 6th reported case of small cell lung cancer-associated acute Guillain-Barre-like syndrome and the first report about an association with a coin-like peripheral pattern. PMID:26039124

  13. Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype.

    PubMed

    Suzuki, Toshio; Tada, Yuji; Nishimura, Rintaro; Kawasaki, Takeshi; Sekine, Ayumi; Urushibara, Takashi; Kato, Fumiaki; Kinoshita, Taku; Ikari, Jun; West, James; Tatsumi, Koichiro

    2016-06-01

    Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs. PMID:27106288

  14. Human resistin promotes neutrophil proinflammatory activation and neutrophil extracellular trap formation and increases severity of acute lung injury.

    PubMed

    Jiang, Shaoning; Park, Dae Won; Tadie, Jean-Marc; Gregoire, Murielle; Deshane, Jessy; Pittet, Jean Francois; Abraham, Edward; Zmijewski, Jaroslaw W

    2014-05-15

    Although resistin was recently found to modulate insulin resistance in preclinical models of type II diabetes and obesity, recent studies also suggested that resistin has proinflammatory properties. We examined whether the human-specific variant of resistin affects neutrophil activation and the severity of LPS-induced acute lung injury. Because human and mouse resistin have distinct patterns of tissue distribution, experiments were performed using humanized resistin mice that exclusively express human resistin (hRTN(+/-)(/-)) but are deficient in mouse resistin. Enhanced production of TNF-α or MIP-2 was found in LPS-treated hRtn(+/-/-) neutrophils compared with control Rtn(-/-/-) neutrophils. Expression of human resistin inhibited the activation of AMP-activated protein kinase, a major sensor and regulator of cellular bioenergetics that also is implicated in inhibiting inflammatory activity of neutrophils and macrophages. In addition to the ability of resistin to sensitize neutrophils to LPS stimulation, human resistin enhanced neutrophil extracellular trap formation. In LPS-induced acute lung injury, humanized resistin mice demonstrated enhanced production of proinflammatory cytokines, more severe pulmonary edema, increased neutrophil extracellular trap formation, and elevated concentration of the alarmins HMGB1 and histone 3 in the lungs. Our results suggest that human resistin may play an important contributory role in enhancing TLR4-induced inflammatory responses, and it may be a target for future therapies aimed at reducing the severity of acute lung injury and other inflammatory situations in which neutrophils play a major role. PMID:24719460

  15. A coin-like peripheral small cell lung carcinoma associated with acute paraneoplastic axonal Guillain-Barre-like syndrome.

    PubMed

    Jung, Ioan; Gurzu, Simona; Balasa, Rodica; Motataianu, Anca; Contac, Anca Otilia; Halmaciu, Ioana; Popescu, Septimiu; Simu, Iunius

    2015-06-01

    A 65-year-old previously healthy male heavy smoker was hospitalized with a 2-week history of progressive muscle weakness in the lower and upper extremities. After 10 days of hospitalization, urinary sphincter incompetence and fecal incontinence were added and tetraparesis was established. The computer-tomography scan examination revealed a massive right hydrothorax and multifocal solid acinar structures with peripheral localization in the left lung, which suggested pulmonary cancer. Bone marrow metastases were also suspected. Based on the examination results, the final diagnosis was acute paraneoplastic axonal Guillain-Barre-like syndrome. The patient died 3 weeks after hospitalization. At autopsy, bronchopneumonia and a right hydrothorax were confirmed. Several 4 to 5-mm-sized round peripherally located white nodules were identified in the left lung, without any central tumor mass. Under microscope, a coin-shaped peripheral/subpleural small cell carcinoma was diagnosed, with generalized bone metastases. A huge thrombus in the abdominal aorta and acute pancreatitis was also seen at autopsy. This case highlights the difficulty of diagnosis of lung carcinomas and the necessity of a complex differential diagnosis of severe progressive ascending neuropathies. This is the 6th reported case of small cell lung cancer-associated acute Guillain-Barre-like syndrome and the first report about an association with a coin-like peripheral pattern. PMID:26039124

  16. Stem/progenitor cells in endogenous repairing responses: new toolbox for the treatment of acute lung injury.

    PubMed

    Yang, Ce; Jiang, Jianxin; Yang, Xuetao; Wang, Haiyan; Du, Juan

    2016-01-01

    The repair of organs and tissues has stepped into a prospective era of regenerative medicine. However, basic research and clinical practice in the lung regeneration remains crawling. Owing to the complicated three dimensional structures and above 40 types of pulmonary cells, the regeneration of lung tissues becomes a great challenge. Compelling evidence has showed that distinct populations of intrapulmonary and extrapulmonary stem/progenitor cells can regenerate epithelia as well as endothelia in various parts of the respiratory tract. Recently, the discovery of human lung stem cells and their relevant studies has opened the door of hope again, which might put us on the path to repair our injured body parts, lungs on demand. Herein, we emphasized the role of endogenous and exogenous stem/progenitor cells in lungs as well as artificial tissue repair for the injured lungs, which constitute a marvelous toolbox for the treatment of acute lung injury. Finally, we further discussed the potential problems in the pulmonary remodeling and regeneration. PMID:26865361

  17. Immunologic Evaluation of Drug Allergy

    PubMed Central

    Gómez, Enrique; Torres, Maria Jose; Mayorga, Cristobalina

    2012-01-01

    Hypersensitivity drug reactions (HDR) consist of an individual abnormal response with the involvement of the immunological system. In addition to specific immunological mechanisms where specific antibodies or sensitised T cells participate, release of inflammatory mediators by non-specific immunological recognition may also occur. Within this category are one of the most common groups of drugs, the non-steroidal anti-inflammatory drugs. In addition to chemical drugs new emerging ones with an increasing protagonism are biological agents like humanised antibodies and others. For IgE dependent reactions both in vivo and in vitro tests can be used for the immunological evaluation. Sensitivity of these is not optimal and very often a drug provocation test must be considered for knowing the mechanism involved and/or establishing the diagnosis. For non-immediate reactions also both in vivo and in vitro tests can be used. Sensitivity for in vivo tests is generally low and in vitro tests may be needed for the immunological evaluation. Immunohistochemical studies of the affected tissue enable a more precise classification of non-immediate reactions. The monitorization of the acute response of the reactions has given clues for understanding these reactions and has promising results for the future of the immunological evaluation of HDR. PMID:22950030

  18. Fatal obstructive lung disease after haploidentical sibling cord blood transplantation.

    PubMed

    Ohnuma, K; Toyoda, Y; Ishida, Y; Honda, K; Nagao, T; Ijiri, R; Tanaka, Y; Goto, K; Hiroki, K; Kigasawa, H; Nishihira, H

    1998-05-01

    We report the case of a patient with fatal obstructive lung disease after an HLA-haploidentical sibling cord blood transplant (CBT), with severe acute GVHD. A 2-year-old girl developed expiratory air trapping gradually with acute and chronic GVHD after CBT for the treatment of ALL. Anti-CMV and immunosuppressive therapy were ineffective, and the patient died of progressive respiratory acidosis. Necropsy of the lung revealed severe bronchiolitis obliterans with cytomegalic inclusion cells in the granulation tissues of the bronchiolitis. Thus, immunologic and GVHD problems can occur even in CBT. PMID:9613788

  19. Acute fibrinous and organizing pneumonia associated with influenza A/H1N1 pneumonia after lung transplantation

    PubMed Central

    2013-01-01

    Background Immunocompromised patients, particularly after lung transplantation, are at high risk to develop atypical forms of pulmonary infections including influenza A/H1N1. Acute Fibrinous and Organizing Pneumonia (AFOP) is a special histological pattern in acute respiratory failure with high mortality. Case presentation We describe a 66-year-old woman with double lung transplantation in August 2009 due to end stage pulmonary fibrosis. After prolonged weaning and subsequent promising course, she developed atypical pneumonia with diffuse pulmonary infiltrates in both lungs in January 2010. Infection with influenza A/H1N1 virus was verified. The patient rapidly suffered from respiratory insufficiency and died eight days after this diagnosis. The post-mortem revealed especially in the lower parts of the lungs the classical histological pattern of pure AFOP. Molecular analyses of lung tissue were positive for influenza A/H1N1. Conclusion To our knowledge we present the first case of AFOP triggered by viral infection, here proven to be influenza virus A/H1N1. Thus, also in the setting of viral infection the highly deadly differential diagnosis of AFOP must be considered. PMID:23683442

  20. B7H3 ameliorates LPS-induced acute lung injury via attenuation of neutrophil migration and infiltration

    PubMed Central

    Li, Yan; Huang, Jie; Foley, Niamh M.; Xu, Yunyun; Li, Yi Ping; Pan, Jian; Redmond, H. Paul; Wang, Jiang Huai; Wang, Jian

    2016-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by an excessive inflammatory response within the lungs and severely impaired gas exchange resulting from alveolar-capillary barrier disruption and pulmonary edema. The costimulatory protein B7H3 functions as both a costimulator and coinhibitor to regulate the adaptive and innate immune response, thus participating in the development of microbial sepsis and pneumococcal meningitis. However, it is unclear whether B7H3 exerts a beneficial or detrimental role during ALI. In the present study we examined the impact of B7H3 on pulmonary inflammatory response, polymorphonuclear neutrophil (PMN) influx, and lung tissue damage in a murine model of lipopolysaccharide (LPS)-induced direct ALI. Treatment with B7H3 protected mice against LPS-induced ALI, with significantly attenuated pulmonary PMN infiltration, decreased lung myeloperoxidase (MPO) activity, reduced bronchoalveolar lavage fluid (BALF) protein content, and ameliorated lung pathological changes. In addition, B7H3 significantly diminished LPS-stimulated PMN chemoattractant CXCL2 production by inhibiting NF-κB p65 phosphorylation, and substantially attenuated LPS-induced PMN chemotaxis and transendothelial migration by down-regulating CXCR2 and Mac-1 expression. These results demonstrate that B7H3 substantially ameliorates LPS-induced ALI and this protection afforded by B7H3 is predominantly associated with its inhibitory effect on pulmonary PMN migration and infiltration. PMID:27515382

  1. B7H3 ameliorates LPS-induced acute lung injury via attenuation of neutrophil migration and infiltration.

    PubMed

    Li, Yan; Huang, Jie; Foley, Niamh M; Xu, Yunyun; Li, Yi Ping; Pan, Jian; Redmond, H Paul; Wang, Jiang Huai; Wang, Jian

    2016-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by an excessive inflammatory response within the lungs and severely impaired gas exchange resulting from alveolar-capillary barrier disruption and pulmonary edema. The costimulatory protein B7H3 functions as both a costimulator and coinhibitor to regulate the adaptive and innate immune response, thus participating in the development of microbial sepsis and pneumococcal meningitis. However, it is unclear whether B7H3 exerts a beneficial or detrimental role during ALI. In the present study we examined the impact of B7H3 on pulmonary inflammatory response, polymorphonuclear neutrophil (PMN) influx, and lung tissue damage in a murine model of lipopolysaccharide (LPS)-induced direct ALI. Treatment with B7H3 protected mice against LPS-induced ALI, with significantly attenuated pulmonary PMN infiltration, decreased lung myeloperoxidase (MPO) activity, reduced bronchoalveolar lavage fluid (BALF) protein content, and ameliorated lung pathological changes. In addition, B7H3 significantly diminished LPS-stimulated PMN chemoattractant CXCL2 production by inhibiting NF-κB p65 phosphorylation, and substantially attenuated LPS-induced PMN chemotaxis and transendothelial migration by down-regulating CXCR2 and Mac-1 expression. These results demonstrate that B7H3 substantially ameliorates LPS-induced ALI and this protection afforded by B7H3 is predominantly associated with its inhibitory effect on pulmonary PMN migration and infiltration. PMID:27515382

  2. Intravenous Immunoglobulin Prevents Murine Antibody-Mediated Acute Lung Injury at the Level of Neutrophil Reactive Oxygen Species (ROS) Production

    PubMed Central

    Semple, John W.; Kim, Michael; Hou, Jing; McVey, Mark; Lee, Young Jin; Tabuchi, Arata; Kuebler, Wolfgang M.; Chai, Zhong-Wei; Lazarus, Alan H.

    2012-01-01

    Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-associated mortality that can occur with any type of transfusion and is thought to be primarily due to donor antibodies activating pulmonary neutrophils in recipients. Recently, a large prospective case controlled clinical study of cardiac surgery patients demonstrated that despite implementation of male donors, a high incidence of TRALI still occurred and suggested a need for additional interventions in susceptible patient populations. To examine if intravenous immunoglobulin (IVIg) may be effective, a murine model of antibody-mediated acute lung injury that approximates human TRALI was examined. When BALB/c mice were injected with the anti-major histocompatibility complex class I antibody 34-1-2s, mild shock (reduced rectal temperature) and respiratory distress (dyspnea) were observed and pre-treatment of the mice with 2 g/kg IVIg completely prevented these symptoms. To determine IVIg's usefulness to affect severe lung damage, SCID mice, previously shown to be hypersensitive to 34-1-2s were used. SCID mice treated with 34-1-2s underwent severe shock, lung damage (increased wet/dry ratios) and 40% mortality within 2 hours. Treatment with 2 g/kg IVIg 18 hours before 34-1-2s administration completely protected the mice from all adverse events. Treatment with IVIg after symptoms began also reduced lung damage and mortality. While the prophylactic IVIg administration did not affect 34-1-2s-induced pulmonary neutrophil accumulation, bone marrow-derived neutrophils from the IVIg-treated mice displayed no spontaneous ROS production nor could they be stimulated in vitro with fMLP or 34-1-2s. These results suggest that IVIg prevents murine antibody-mediated acute lung injury at the level of neutrophil ROS production and thus, alleviating tissue damage. PMID:22363629

  3. Immunological and respiratory findings in spice-factory workers.

    PubMed

    Zuskin, E; Kanceljak, B; Skuric, Z; Pokrajac, D; Schachter, E N; Witek, T J; Maayani, S

    1988-10-01

    Immunological and respiratory findings were studied in a group of 45 female spice-factory workers (mean age: 39 years; mean exposure: 17 years). In addition a group of 45 female control workers matched by sex, age, and smoking habit were also studied. Intradermal skin testing with mixed spice dust allergen demonstrated positive skin reactions in 73.3% of exposed and in 33.3% of control workers (P less than 0.001). Increased IgE serum levels were found in 36.8% of exposed and in 9.7% of the control workers (P less than 0.01). The prevalence of chronic respiratory symptoms was significantly higher in the exposed workers than in the control workers (P less than 0.01). There was, however, no consistent correlation between skin reactivity and chronic respiratory symptoms. There was a high prevalence of acute symptoms during the work shift. These complaints were more frequent in workers with positive skin tests for the symptoms of cough, chest tightness, and irritated and dry throat. Ventilatory capacity was measured by recording maximum expiratory flow-volume (MEFV) curves. There were statistically significant mean reductions during the work shift for all measured lung function parameters in workers with positive skin reactions. In those workers with negative skin reactions only FEF50 and FEF25 reached statistical significance. Aqueous extracts of different spices (chilli pepper, paprika, caraway, coriander leaves, coriander seeds, cinnamon, ginger, onion, curry, and parsley) caused a dose-related contractile response of isolated guinea pig tracheal smooth muscle. These data suggest that immunologic reactions to spices are frequent in spice workers and may be related to acute symptoms and lung function changes, but not to chronic changes. The data further suggest that, in addition to any immunologic response these spices may produce in vivo, they probably also provoke direct irritant reactions in the airways as suggested by in vitro data. PMID:3168968

  4. Sex-specific Differences in Hyperoxic Lung Injury in Mice: Implications for Acute and Chronic Lung Disease in Humans

    PubMed Central

    Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua; Couroucli, Xanthi I.; Barrios, Roberto; Moorthy, Bhagavatula

    2014-01-01

    Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO2>0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF 2α) (LC-MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. CytochromeP450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F>M) and VEGF (M>F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans. PMID:23792423

  5. Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: a potential mechanism underlying adult respiratory distress syndrome.

    PubMed

    Gongora, Maria Carolina; Lob, Heinrich E; Landmesser, Ulf; Guzik, Tomasz J; Martin, W David; Ozumi, Kiyoski; Wall, Susan M; Wilson, David Scott; Murthy, Niren; Gravanis, Michael; Fukai, Tohru; Harrison, David G

    2008-10-01

    The extracellular superoxide dismutase 3 (SOD3) is highly expressed in both blood vessels and lungs. In different models of pulmonary injury, SOD3 is reduced; however, it is unclear whether this contributes to lung injury. To study the role of acute SOD3 reduction in lung injury, the SOD3 gene was deleted in adult mice by using the Cre-Lox technology. Acute reduction of SOD3 led to a fivefold increase in lung superoxide, marked inflammatory cell infiltration, a threefold increase in the arterial-alveolar gradient, respiratory acidosis, histological changes similar to those observed in adult respiratory distress syndrome, and 85% mortality. Treatment with the SOD mimetic MnTBAP and intranasal administration of SOD-containing polyketal microparticles reduced mortality, prevented the histological alterations, and reduced lung superoxide levels. To understand how mice with the SOD3 embryonic deletion survived without lung injury, gene array analysis was performed. These data demonstrated the up-regulation of 37 genes and down-regulation of nine genes, including those involved in cell signaling, inflammation, and gene transcription in SOD3-/- mice compared with either mice with acute SOD3 reduction or wild-type controls. These studies show that SOD3 is essential for survival in the presence of ambient oxygen and that acute loss of this enzyme can lead to severe lung damage. Strategies either to prevent SOD3 inactivation or to augment its levels might prove useful in the treatment of acute lung injury. PMID:18787098

  6. Fibroblast Growth Factor-10 (FGF-10) Mobilizes Lung-resident Mesenchymal Stem Cells and Protects Against Acute Lung Injury

    PubMed Central

    Tong, Lin; Zhou, Jian; Rong, Linyi; Seeley, Eric J.; Pan, Jue; Zhu, Xiaodan; Liu, Jie; Wang, Qin; Tang, Xinjun; Qu, Jieming; Bai, Chunxue; Song, Yuanlin

    2016-01-01

    FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs. PMID:26869337

  7. Sarcoidosis: Immunopathogenesis and Immunological Markers

    PubMed Central

    Loke, Wei Sheng Joshua; Herbert, Cristan; Thomas, Paul S.

    2013-01-01

    Sarcoidosis is a multisystem granulomatous disorder invariably affecting the lungs. It is a disease with noteworthy variations in clinical manifestation and disease outcome and has been described as an “immune paradox” with peripheral anergy despite exaggerated inflammation at disease sites. Despite extensive research, sarcoidosis remains a disease with undetermined aetiology. Current evidence supports the notion that the immune response in sarcoidosis is driven by a putative antigen in a genetically susceptible individual. Unfortunately, there currently exists no reliable biomarker to delineate the disease severity and prognosis. As such, the diagnosis of sarcoidosis remains a vexing clinical challenge. In this review, we outline the immunological features of sarcoidosis, discuss the evidence for and against various candidate etiological agents (infective and noninfective), describe the exhaled breath condensate, a novel method of identifying immunological biomarkers, and suggest other possible immunological biomarkers to better characterise the immunopathogenesis of sarcoidosis. PMID:26464848

  8. Acute Lung Injury Is Reduced in fat-1 Mice Endogenously Synthesizing n-3 Fatty Acids

    PubMed Central

    Mayer, Konstantin; Kiessling, Almuth; Ott, Juliane; Schaefer, Martina Barbara; Hecker, Matthias; Henneke, Ingrid; Schulz, Richard; Günther, Andreas; Wang, Jingdong; Wu, Lijun; Roth, Joachim; Seeger, Werner; Kang, Jing X.

    2009-01-01

    Rationale: Acute lung injury (ALI) remains an important cause of mortality in intensive care units. Inflammation is controlled by cytokines and eicosanoids derived from the n-6 fatty acid (FA) arachidonic acid (AA). The n-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and mediators derived from EPA and DHA possess reduced inflammatory potency. Objectives: To determine whether the ability of fat-1 mice to endogenously convert n-6 to n-3 FA, and thus generate an increased ratio of n-3 to n-6 FA, impacts experimental ALI. Methods: We investigated ALI induced by intratracheal instillation of endotoxin in fat-1 and wild-type (WT) mice, assessing leukocyte numbers, protein concentration, and prostaglandin and cytokine levels in bronchoalveolar lavage fluid, as well as free FA in plasma, and lung ventilator compliance. Body temperature and motor activity of mice—markers of sickness behavior—were also recorded. Measurements and Main Results: In ALI, fat-1 mice exhibited significantly reduced leukocyte invasion, protein leakage, and macrophage inflammatory protein-2 and thromboxane B2 levels in lavage fluid compared with WT mice. Free AA levels were increased in the plasma of WT mice in response to endotoxin, whereas EPA and DHA were increased in the fat-1 group. Ventilator compliance was significantly improved in fat-1 mice. Body temperature and motor activity were decreased in ALI. fat-1 Mice recovered body temperature and motor activity faster. Conclusions: fat-1 Mice exhibited reduced features of ALI and sickness behavior. Increasing the availability of n-3 FA may thus be beneficial in critically ill patients with ALI. PMID:19136374

  9. Mesenteric lymph duct drainage attenuates acute lung injury in rats with severe intraperitoneal infection.

    PubMed

    Zhang, Yanmin; Zhang, Shukun; Tsui, Naiqiang

    2015-01-01

    The purpose of this study is to investigate the hypothesis that the mesenteric lymphatic system plays an important role in acute lung injury in a rat model induced by severe intraperitoneal infection. Male Wistar rats weighing 250∼300 g were randomly divided into 3 groups and subjected to sham operation, intraperitoneal infection, or mesenteric lymphatic drainage. The activity of diamine oxidase (DAO) and myeloperoxidase (MPO) were measured by enzymatic assay. The endotoxin levels in plasma, lymph, and bronchoalveolar lavage fluid (BALF) were evaluated using the limulus amoebocyte lysate reagent. The cytokines, adhesion factors, chemokines, and inflammatory factors were detected by ELISA. TLR-4, NF-kB, and IRAK-4 were analyzed by Western blotting. Compared with sham-operated rats, rats with intraperitoneal infection had increased MPO and decreased DAO activity in intestinal tissues. Mesenteric lymph drainage reduced the alterations in MPO and DAO activity induced by intraperitoneal infection. The MPO activity in pulmonary tissue and the permeability of pulmonary blood vessels were also increased, which were partially reversed by mesenteric lymph drainage. The endotoxin levels in lymphatic fluid and alveolar perfusion fluid were elevated after intraperitoneal infection but decreased to control levels after lymph drainage. No alterations in the levels of plasma endotoxin were observed. The number of neutrophils was increased in BALF and lymph in the infected rats, and was also reduced after drainage. Lymph drainage also decreased the levels of inflammatory cytokines, chemokines, and adhesion factors in the plasma, lymph, and BALF, as well as the levels of TLR-4, NF-kB, and IRAK-4 in pulmonary and intestinal tissues. The mesenteric lymphatic system is the main pathway involved in early lung injury caused by severe intraperitoneal infection, in which activation of the TLR-4 signal pathway may play a role. PMID:25537798

  10. Association of Nrf2 Polymorphism Haplotypes with Acute Lung Injury Phenotypes in Inbred Strains of Mice

    PubMed Central

    Jedlicka, Anne E.; Gladwell, Wesley; Marzec, Jacqui; McCaw, Zackary R.; Bienstock, Rachelle J.; Kleeberger, Steven R.

    2015-01-01

    Abstract Aims: Nrf2 is a master transcription factor for antioxidant response element (ARE)-mediated cytoprotective gene induction. A protective role for pulmonary Nrf2 was determined in model oxidative disorders, including hyperoxia-induced acute lung injury (ALI). To obtain additional insights into the function and genetic regulation of Nrf2, we assessed functional single nucleotide polymorphisms (SNPs) of Nrf2 in inbred mouse strains and tested whether sequence variation is associated with hyperoxia susceptibility. Results: Nrf2 SNPs were compiled from publicly available databases and by re-sequencing DNA from inbred strains. Hierarchical clustering of Nrf2 SNPs categorized the strains into three major haplotypes. Hyperoxia susceptibility was greater in haplotypes 2 and 3 strains than in haplotype 1 strains. A promoter SNP −103 T/C adding an Sp1 binding site in haplotype 2 diminished promoter activation basally and under hyperoxia. Haplotype 3 mice bearing nonsynonymous coding SNPs located in (1862 A/T, His543Gln) and adjacent to (1417 T/C, Thr395Ile) the Neh1 domain showed suppressed nuclear transactivation of pulmonary Nrf2 relative to other strains, and overexpression of haplotype 3 Nrf2 showed lower ARE responsiveness than overexpression of haplotype 1 Nrf2 in airway cells. Importantly, we found a significant correlation of Nrf2 haplotypes and hyperoxic lung injury phenotypes. Innovation and Conclusion: The results indicate significant influence of Nrf2 polymorphisms and haplotypes on gene function and hyperoxia susceptibility. Our findings further support Nrf2 as a genetic determinant in ALI pathogenesis and provide useful tools for investigators who use mouse strains classified by Nrf2 haplotypes to elucidate the role for Nrf2 in oxidative disorders. Antioxid. Redox Signal. 22, 325–338. PMID:25268541

  11. Clausena anisata-mediated protection against lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Jeon, Chan-Mi; Shin, In-Sik; Shin, Na-Rae; Hong, Ju-Mi; Kwon, Ok-Kyoung; Kim, Jung-Hee; Oh, Sei-Ryang; Bach, Tran-The; Hai, Do-Van; Quang, Bui-Hong; Choi, Sang-Ho; Lee, Joongku; Myung, Pyung-Keun; Ahn, Kyung-Seop

    2016-04-01

    Clausena anisata (Willd.) Hook.f. ex Benth. (CA), which is widely used in traditional medicine, reportedly exerts antitumor, anti-inflammatory and other important therapeutic effects. The aim of the present study was to investigate the potential therapeutic effects of CA in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) and in LPS-stimulated RAW 264.7 cells. Male C57BL/6 mice were administered treatments for 3 days by oral gavage. On day 3, the mice were instilled intranasally with LPS or PBS followed 3 h later by oral CA (30 mg/kg) or vehicle administration. In vitro, CA decreased nitric oxide (NO) production and pro-inflammatory cytokines, such as interleukin (IL)-6 and prostaglandin E2 (PGE2), in LPS-stimulated RAW 264.7 cells. CA also reduced the expression of pro-inflammatory mediators, such as cyclooxygenase-2. In vivo, CA administration significantly reduced inflammatory cell numbers in the bronchoalveolar lavage fluid (BALF) and suppressed pro-inflammatory cytokine levels, including tumor necrosis factor-α (TNF-α), IL-6, and IL-1β, as well as reactive oxygen species production in the BALF. CA also effectively reduced airway inflammation in mouse lung tissue of an LPS-induced ALI mouse model, in addition to decreasing inhibitor κB (IκB) and nuclear factor-κB (NF-κB) p65 phosphorylation. Taken together, the findings demonstrated that CA inhibited inflammatory responses in a mouse model of LPS-induced ALI and in LPS-stimulated RAW 264.7 cells. Thus, CA is a potential candidate for development as an adjunctive treatment for inflammatory disorders, such as ALI. PMID:26952971

  12. TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants

    PubMed Central

    2014-01-01

    Background Inhalation of TIP peptides that mimic the lectin-like domain of TNF-α is a novel approach to attenuate pulmonary oedema on the threshold to clinical application. A placebo-controlled porcine model of acute respiratory distress syndrome (ARDS) demonstrated a reduced thermodilution-derived extravascular lung water index (EVLWI) and improved gas exchange through TIP peptide inhalation within three hours. Based on these findings, the present study compares a single versus a repetitive inhalation of a TIP peptide (TIP-A) and two alternate peptide versions (TIP-A, TIP-B). Methods Following animal care committee approval ARDS was induced by bronchoalveolar lavage followed by injurious ventilation in 21 anaesthetized pigs. A randomised-blinded three-group setting compared the single-dosed peptide variants TIP-A and TIP-B as well as single versus repetitive inhalation of TIP-A (n = 7 per group). Over two three-hour intervals parameters of gas exchange, transpulmonary thermodilution, calculated alveolar fluid clearance, and ventilation/perfusion-distribution were assessed. Post-mortem measurements included pulmonary wet/dry ratio and haemorrhage/congestion scoring. Results The repetitive TIP-A inhalation led to a significantly lower wet/dry ratio than a single dose and a small but significantly lower EVLWI. However, EVLWI changes over time and the derived alveolar fluid clearance did not differ significantly. The comparison of TIP-A and B showed no relevant differences. Gas exchange and ventilation/perfusion-distribution significantly improved in all groups without intergroup differences. No differences were found in haemorrhage/congestion scoring. Conclusions In comparison to a single application the repetitive inhalation of a TIP peptide in three-hour intervals may lead to a small additional reduction the lung water content. Two alternate TIP peptide versions showed interchangeable characteristics. PMID:24904234

  13. Gastroesophageal Reflux Disease Is Associated With an Increased Rate of Acute Rejection in Lung Transplant Allografts

    PubMed Central

    Shah, N.S.; Force, S.D.; Mitchell, P.O.; Lin, E.; Lawrence, E.C.; Easley, K.; Qian, J.; Ramirez, A.; Neujahr, D.C.; Gal, A.; Leeper, K.; Pelaez, A.

    2012-01-01

    Purpose Gastric fundoplication (GF) for gastroesophageal reflux disease (GERD) may protect against the progression of chronic rejection in lung transplant (LT) recipients. However, the association of GERD with acute rejection episodes (ARE) is uncertain. This study sought to identify if ARE were linked to GERD in LT patients. Methods This single-center retrospective observational study, of patients transplanted from January 1, 2000, to January 31, 2009, correlated results of pH probe testing for GERD with ARE (≥International Society for Heart and Lung Transplantation A1 or B1). We compared the rates of ARE among patients with GERD (DeMeester Score > 14.7) versus without GERD as number of ARE per 1,000 patient-days after LT. Patients undergoing GF prior to LT were excluded. Results The analysis included 60 LT subjects and 9,249 patient-days: 33 with GERD versus 27 without GERD. We observed 51 ARE among 60 LT recipients. The rate of ARE was highest among patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 (P = .00016). Upon multivariate negative binomial regression modeling, only GERD was associated with ARE (IDR 2.15; P = .009). Furthermore, GERD was associated with multiple ARE (36.4% vs 0%; P < .0001) and earlier onset compared with patients without GERD: ARE proportion at 2 months was 0.55 versus 0.26 P = .004). Conclusion In LT recipients, GERD was associated with a higher rate, multiple events, and earlier onset of ARE. The efficacy of GF to reduce ARE among patients with GERD needs further evaluation. PMID:20832573

  14. Assessment of inhaled acute ammonia-induced lung injury in rats.

    PubMed

    Perkins, Michael W; Wong, Benjamin; Tressler, Justin; Coggins, Andrew; Rodriguez, Ashley; Devorak, Jennifer; Sciuto, Alfred M

    2016-01-01

    This study examined acute toxicity and lung injury following inhalation exposure to ammonia. Male Sprague-Dawley rats (300-350 g) were exposed to 9000, 20,000, 23,000, 26,000, 30,000 or 35,000 ppm of ammonia for 20 min in a custom head-out exposure system. The exposure atmosphere, which attained steady state within 3 min for all ammonia concentrations, was monitored and verified using a Fourier transform infrared spectroscopy (FTIR) gas analyzer. Animals exposed to ammonia resulted in dose-dependent increases in observed signs of intoxication, including increased chewing and licking, ocular irritation, salivation, lacrimation, oronasal secretion and labored breathing. The LCt50 of ammonia within this head-out inhalation exposure model was determined by probit analysis to be 23,672 ppm (16,489 mg/m(3)) for the 20 min exposure in male rats. Exposure to 20,000 or 23,000 ppm of ammonia resulted in significant body weight loss 24-h post-exposure. Lung edema increased in all ammonia-exposed animal groups and was significant following exposure to 9000 ppm. Bronchoalveolar fluid (BALF) protein concentrations significantly increased following exposure to 20,000 or 23,000 ppm of ammonia in comparison to controls. BAL cell (BALC) death and total cell counts increased in animals exposed to 20,000 or 23,000 ppm of ammonia in comparison to controls. Differential cell counts of white blood cells, neutrophils and platelets from blood and BALF were significantly increased following exposure to 23,000 ppm of ammonia. The following studies describe the validation of a head-out inhalation exposure model for the determination of acute ammonia-induced toxicity; this model will be used for the development and evaluation of potential therapies that provide protection against respiratory and systemic toxicological effects. PMID:26821737

  15. Immunological complications of blood transfusions.

    PubMed

    Brand, Anneke

    2016-01-01

    Most adverse blood transfusion (BT) events are immune-mediated and in the majority of severe reactions antibodies can be identified as causal factors. Alloimmunization not only causes symptomatic reactions, transfused cells can also be (silently) destroyed. Immunization by BT can contribute to hemolytic disease of the newborn as well as to allograft rejection after transplantation. Reversely, pregnancy and transplantation may evoke immunity hampering transfusion therapy. Besides causing mortality and morbidity, alloimmunization has a huge economic impact. Transfusion reactions prolong hospital stay, require diagnostic tests and complex donor selection procedures and create the need for typed donor registries. In the 1970s, Opeltz and colleagues described that pre-transplantation BT impaired rejection of renal transplants. Leukocytes were essential for this immunosuppressive BT effect that raised concern about negative effects on cancer growth and resistance against infections. Studies on the mechanism were however preliminary abandoned when calcineurin inhibitors for prevention of graft rejection became available and since all blood products underwent leukoreduction in most countries as precautionary measure against transmission of variant Creutzfeldt-Jacob disease. Whether current leukoreduced BT are immunosuppressive and for which patients or circumstances this may contribute to worse outcome, is unknown. The last decades of the previous century, leukoreduction of cellular blood products for leukemia patients significantly reduced the incidence of immunological platelet transfusion refractoriness. The first decade of this century the avoidance of plasma- and platelet-products from females, that may contain donor-derived leukocyte antibodies, decreased transfusion related acute lung injury (TRALI) by more than 30%. These were major achievements. Challenge for the near future is to further reduce alloimmunization in particular against red blood cells (RBC) as a

  16. Transfusion Related Acute Lung Injury (TRALI): A Single Institution Experience of 15 Years.

    PubMed

    Kumar, Ramesh; Sedky, Mohammed Jaber; Varghese, Sunny Joseph; Sharawy, Osama Ebrahim

    2016-09-01

    Transfusion related acute Lung injury (TRALI) though a serious blood transfusion reaction with a fatality rate of 5-25 % presents with acute respiratory distress with hypoxaemia and noncardiac pulmonary oedema within 6 h of transfusion. In non fatal cases, it may resolve within 72 h or earlier. Although reported with an incidence of 1:5000, its true occurrence is rather unknown. Pathogenesis is believed to be related to sequestration and adhesion of neutrophils to the pulmonary capillary endothelium and its activation leading to its destruction and leaks. The patient's underlying condition, anti-neutrophil antibody in the transfused donor plasma and certain lipids that accumulate in routinely stores blood and components are important in its aetiopathogenesis. Patient's predisposing conditions include haematological malignancy, major surgery (especially cardiac), trauma and infections. The more commonly incriminated products include fresh frozen plasma (FFP), platelets (whole blood derived and apheresis), whole blood and Packed RBC. Occasional cases involving cryoprecipitate and Intravenous immunoglobulin (IVig) have also been reported. We present a 15 year single institution experience of TRALI, during which we observed 9 cases among 170,871 transfusions, giving an incidence of 1:19,000. We did not encounter cases of haematological malignancy or cardiac surgery in our TRALI patients. Among the blood products, that could be related to TRALI in our patients included solitary cases receiving cryoprecipitate, IVIg, and recombinant Factor VII apart from platelets and FFP. All patients were treated with oxygen support. Six patients required mechanical ventilation. Off label hydrocortisone was given to all patients. There were no cases of fatality among our patients. PMID:27429525

  17. Recipient Clinical Risk Factors Predominate in Possible Transfusion-Related Acute Lung Injury

    PubMed Central

    Toy, Pearl; Bacchetti, Peter; Grimes, Barbara; Gajic, Ognjen; Murphy, Edward L.; Winters, Jeffrey L.; Gropper, Michael A.; Hubmayr, Rolf D.; Matthay, Michael A.; Wilson, Gregory; Koenigsberg, Monique; Lee, Deanna C.; Hirschler, Nora V.; Lowell, Clifford A.; Schuller, Randy M.; Gandhi, Manish J.; Norris, Philip J.; Mair, David C.; Rosen, Rosa Sanchez; Looney, Mark R.

    2014-01-01

    Background Possible transfusion-related acute lung injury (pTRALI) cases by definition have a clear temporal relationship to an alternative recipient risk factor for acute respiratory distress syndrome (ARDS). We questioned whether transfusion factors are important for the development of pTRALI. Study Design and Methods In this nested case-control study, we prospectively identified 145 consecutive patients with pTRALI and randomly selected 163 transfused controls over a 4-year period at the University of California, San Francisco and the Mayo Clinic, Rochester. Results For pTRALI, we found evidence against transfusion being important: receipt of plasma from female donors (OR 0.82, 95% CI 0.29 – 2.3, p=0.70), total number of units transfused (OR 0.99, 95% CI 0.89 – 1.10, p=0.86), and number of red blood cell and whole blood units transfused (OR 0.78, 95% CI 0.59 –1.03, p=0.079). In contrast, we found that risk for pTRALI was associated with additional recipient factors: chronic alcohol abuse (OR 12.5, 95% CI 2.8 – 55, p<0.001), current smoker (OR 4.2, 95% CI 1.67 – 10.8, p=0.0024), shock before transfusion (OR 4.6, 95% CI 2.0 – 10.7, p<0.001), and positive fluid balance before transfusion (OR 1.32 per liter, 95% CI 1.20 – 1.44, p<0.001). Conclusion Recipient risk factors for ARDS rather than transfusion risk factors predominate in pTRALI. PMID:25488517

  18. Picrasma quassiodes (D. Don) Benn. attenuates lipopolysaccharide (LPS)-induced acute lung injury.

    PubMed

    Lee, Jae-Won; Park, Ji-Won; Shin, Na-Rae; Park, So-Yeon; Kwon, Ok-Kyoung; Park, Hyun Ah; Lim, Yourim; Ryu, Hyung Won; Yuk, Heung Joo; Kim, Jung Hee; Oh, Sei-Ryang; Ahn, Kyung-Seop

    2016-09-01

    Picrasma quassiodes (D.Don) Benn. (PQ) is a medicinal herb belonging to the family Simaroubaceae and is used as a traditional herbal remedy for various diseases. In this study, we evaluated the effects of PQ on airway inflammation using a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) and LPS-stimulated raw 264.7 cells. ALI was induced in C57BL/6 mice by the intranasal administration of LPS, and PQ was administered orally 3 days prior to exposure to LPS. Treatment with PQ significantly attenuated the infiltration of inflammatory cells in the bronchoalveolar lavage fluid (BALF). PQ also decreased the production of reactive oxygen species (ROS) and pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 in BALF. In addition, PQ inhibited airway inflammation by reducing the expression of inducible nitric oxide synthase (iNOS) and by increasing the expression of heme oxygenase-1 (HO-1) in the lungs. Furthermore, we demonstrated that PQ blocked the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in the lungs of mice with LPS-induced ALI. In the LPS-stimulated RAW 264.7 cells, PQ inhibited the release of pro-inflammatory cytokines and increased the mRNA expression of monocyte chemoattractant protein-1 (MCP-1). Treatment with PQ decreased the translocation of nuclear factor (NF)-κB to the nucleus, and increased the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and the expression of HO-1. PQ also inhibited the activation of p38 in the LPS-stimulated RAW 264.7 cells. Taken together, our findings demonstrate that PQ exerts anti-inflammatory effects against LPS-induced ALI, and that these effects are associated with the modulation of iNOS, HO-1, NF-κB and MAPK signaling. Therefore, we suggest that PQ has therapeutic potential for use in the treatment of ALI. PMID:27431288

  19. GADD45a Promoter Regulation by a Functional Genetic Variant Associated with Acute Lung Injury

    PubMed Central

    Mitra, Sumegha; Wade, Michael S.; Sun, Xiaoguang; Moldobaeva, Nurgul; Flores, Carlos; Ma, Shwu-Fan; Zhang, Wei

    2014-01-01

    Rationale Growth arrest DNA damage inducible alpha (GADD45a) is a stress-induced gene we have shown to participate in the pathophysiology of ventilator-induced lung injury (VILI) via regulation of mechanical stress-induced Akt ubiquitination and phosphorylation. The regulation of GADD45a expression by mechanical stress and its relationship with acute lung injury (ALI) susceptibility and severity, however, remains unknown. Objectives We examined mechanical stress-dependent regulatory elements (MSRE) in the GADD45a promoter and the contribution of promoter polymorphisms in GADD45a expression and ALI susceptibility. Methods and Results Initial studies in GADD45a knockout and heterozygous mice confirmed the relationship of GADD45a gene dose to VILI severity. Human lung endothelial cells (EC) transfected with a luciferase vector containing the full length GADD45a promoter sequence (−771 to +223) demonstrated a >4 fold increase in GADD45a expression in response to 18% cyclic stretch (CS, 4 h) compared to static controls while specific promoter regions harboring CS-dependent MSRE were identified using vectors containing serial deletion constructs of the GADD45a promoter. In silico analyses of GADD45a promoter region (−371 to −133) revealed a potential binding site for specificity protein 1 (SP1), a finding supported by confirmed SP1 binding with the GADD45a promoter and by the significant attenuation of CS-dependent GADD45a promoter activity in response to SP1 silencing. Separately, case-control association studies revealed a significant association of a GADD45a promoter SNP at −589 (rs581000, G>C) with reduced ALI susceptibility. Subsequently, we found allelic variation of this SNP is associated with both differential GADD45a expression in mechanically stressed EC (18% CS, 4 h) and differential binding site of interferon regulatory factor 7 (IRF7) at this site. Conclusion These results strongly support a functional role for GADD45a in ALI/VILI and identify a

  20. Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-κB activation

    PubMed Central

    Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

    2010-01-01

    Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-α-evoked translocation of nuclear factor (NF)-κB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-κB and production of TNF-α in mouse macrophage RAW264·7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-α level and inhibited the LPS-evoked nuclear translocation of NF-κB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS. PMID:20030669

  1. Plantamajoside ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-κB and MAPK activation.

    PubMed

    Wu, Haichong; Zhao, Gan; Jiang, Kangfeng; Chen, Xiuying; Zhu, Zhe; Qiu, Changwei; Li, Chengye; Deng, Ganzhen

    2016-06-01

    Despite developments in the knowledge and therapy of acute lung injury in recent decades, mortality remains high, and there is usually a lack of effective therapy. Plantamajoside, a major ingredient isolated from Plantago asiatica L. (Plantaginaceae), has been reported to have potent anti-inflammatory properties. However, the effect of plantamajoside on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice has not been investigated. The present study aimed to reveal the potential mechanism responsible for the anti-inflammatory effects of plantamajoside on LPS-induced acute lung injury in mice and in RAW264.7 cells. The results of histopathological changes as well as the lung wet-to-dry ratio and myeloperoxidase (MPO) activity showed that plantamajoside ameliorated the lung injury that was induced by LPS. qPCR and ELISA assays demonstrated that plantamajoside suppressed the production of IL-1β, IL-6 and TNF-α in a dose-dependent manner. TLR4 is an important sensor in LPS infection. Molecular studies showed that the expression of TLR4 was inhibited by plantamajoside administration. Further study was conducted on nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) using pathways using western blots. The results showed that plantamajoside inhibited the phosphorylation of IκBα, p65, p38, JNK and ERK. All results indicated that plantamajoside has protective effect on LPS-induced ALI in mice and in RAW264.7 cells. Thus, plantamajoside may be a potential therapy for the treatment of pulmonary inflammation. PMID:27089391

  2. Increased Numbers of Circulating CD8 Effector Memory T Cells before Transplantation Enhance the Risk of Acute Rejection in Lung Transplant Recipients

    PubMed Central

    San Segundo, David; Ballesteros, María Ángeles; Naranjo, Sara; Zurbano, Felipe; Miñambres, Eduardo; López-Hoyos, Marcos

    2013-01-01

    The effector and regulatory T cell subpopulations involved in the development of acute rejection episodes in lung transplantation remain to be elucidated. Twenty-seven lung transplant candidates were prospectively monitored before transplantation and within the first year post-transplantation. Regulatory, Th17, memory and naïve T cells were measured in peripheral blood of lung transplant recipients by flow cytometry. No association of acute rejection with number of peripheral regulatory T cells and Th17 cells was found. However, effector memory subsets in acute rejection patients were increased during the first two months post-transplant. Interestingly, patients waiting for lung transplant with levels of CD8+ effector memory T cells over 185 cells/mm3 had a significant increased risk of rejection [OR: 5.62 (95% CI: 1.08-29.37), p=0.04]. In multivariate analysis adjusted for age and gender the odds ratio for rejection was: OR: 5.89 (95% CI: 1.08-32.24), p=0.04. These data suggest a correlation between acute rejection and effector memory T cells in lung transplant recipients. The measurement of peripheral blood CD8+ effector memory T cells prior to lung transplant may define patients at high risk of acute lung rejection. PMID:24236187

  3. /sup 111/In-platelet and /sup 125/I-fibrinogen deposition in the lungs in experimental acute pancreatitis

    SciTech Connect

    Goulbourne, I.A.; Watson, H.; Davies, G.C.

    1987-12-01

    An experimental model of acute pancreatitis in rats has been used to study intrapulmonary /sup 125/I-fibrinogen and /sup 111/In-platelet deposition. Pancreatitis caused a significant increase in wet lung weight compared to normal, and this could be abolished by heparin or aspirin pretreatment. /sup 125/I-fibrinogen was deposited in the lungs of animals to a significantly greater degree than in controls (P less than 0.01). /sup 125/I-fibrinogen deposition was reduced to control levels by pretreatment with aspirin or heparin (P less than 0.05). The uptake of radiolabeled platelets was greater in pancreatitis than in controls (P less than 0.001). Pancreatitis appears to be responsible for platelet entrapment in the lungs. Platelet uptake was reduced by heparin treatment but unaffected by aspirin therapy.

  4. Reverse-migrated neutrophils regulated by JAM-C are involved in acute pancreatitis-associated lung injury.

    PubMed

    Wu, Deqing; Zeng, Yue; Fan, Yuting; Wu, Jianghong; Mulatibieke, Tunike; Ni, Jianbo; Yu, Ge; Wan, Rong; Wang, Xingpeng; Hu, Guoyong

    2016-01-01

    Junctional adhesion molecule-C (JAM-C) plays a key role in the promotion of the reverse transendothelial migration (rTEM) of neutrophils, which contributes to the dissemination of systemic inflammation and to secondary organ damage. During acute pancreatitis (AP), systemic inflammatory responses lead to distant organ damage and typically result in acute lung injury (ALI). Here, we investigated the role of rTEM neutrophils in AP-associated ALI and the molecular mechanisms by which JAM-C regulates neutrophil rTEM in this disorder. In this study, rTEM neutrophils were identified in the peripheral blood both in murine model of AP and human patients with AP, which elevated with increased severity of lung injury. Pancreatic JAM-C was downregulated during murine experimental pancreatitis, whose expression levels were inversely correlated with both increased neutrophil rTEM and severity of lung injury. Knockout of JAM-C resulted in more severe lung injury and systemic inflammation. Significantly greater numbers of rTEM neutrophils were present both in the circulation and pulmonary vascular washout in JAM-C knockout mice with AP. This study demonstrates that during AP, neutrophils that are recruited to the pancreas may migrate back into the circulation and then contribute to ALI. JAM-C downregulation may contribute to AP-associated ALI via promoting neutrophil rTEM. PMID:26841848

  5. Customization of an open-lung ventilation strategy to treat a case of life-threatening acute respiratory distress syndrome.

    PubMed

    Grooms, David A; Sibole, Stephen H; Tomlinson, James R; Marik, Paul E; Chatburn, Robert L

    2011-04-01

    The ARDS Network low-tidal-volume protocol is considered the standard of care for patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The protocol is built on the foundation of low-tidal-volume ventilation, use of a combined PEEP and F(IO(2)) table, and managing alveolar end-inspiratory pressure by limiting the plateau airway pressure to ≤ 30 cm H(2)O. Although this strategy, to date, is the only method that significantly improves ALI/ARDS survival, alternative methods of improving hypoxemia and minimizing ventilator-induced lung injury, in conjunction with low-tidal-volume ventilation, can be used for life-threatening ARDS. We present a case in which we customized the use of alveolar recruitment maneuvers by analyzing the hysteresis of the pressure-volume curve to assess lung recruitability, decremental PEEP to sustain lung recruitment, and careful use of plateau pressure ≥ 30 cm H(2)O, which improved our patient's life-threatening hypoxemia within the first 36 min of arrival to our ICU. PMID:21255504

  6. Reverse-migrated neutrophils regulated by JAM-C are involved in acute pancreatitis-associated lung injury

    PubMed Central

    Wu, Deqing; Zeng, Yue; Fan, Yuting; Wu, Jianghong; Mulatibieke, Tunike; Ni, Jianbo; Yu, Ge; Wan, Rong; Wang, Xingpeng; Hu, Guoyong

    2016-01-01

    Junctional adhesion molecule-C (JAM-C) plays a key role in the promotion of the reverse transendothelial migration (rTEM) of neutrophils, which contributes to the dissemination of systemic inflammation and to secondary organ damage. During acute pancreatitis (AP), systemic inflammatory responses lead to distant organ damage and typically result in acute lung injury (ALI). Here, we investigated the role of rTEM neutrophils in AP-associated ALI and the molecular mechanisms by which JAM-C regulates neutrophil rTEM in this disorder. In this study, rTEM neutrophils were identified in the peripheral blood both in murine model of AP and human patients with AP, which elevated with increased severity of lung injury. Pancreatic JAM-C was downregulated during murine experimental pancreatitis, whose expression levels were inversely correlated with both increased neutrophil rTEM and severity of lung injury. Knockout of JAM-C resulted in more severe lung injury and systemic inflammation. Significantly greater numbers of rTEM neutrophils were present both in the circulation and pulmonary vascular washout in JAM-C knockout mice with AP. This study demonstrates that during AP, neutrophils that are recruited to the pancreas may migrate back into the circulation and then contribute to ALI. JAM-C downregulation may contribute to AP-associated ALI via promoting neutrophil rTEM. PMID:26841848

  7. Formononetin inhibited the inflammation of LPS-induced acute lung injury in mice associated with induction of PPAR gamma expression.

    PubMed

    Ma, Zhanqiang; Ji, Weiwei; Fu, Qiang; Ma, Shiping

    2013-12-01

    Formononetin has shown a variety of pharmacologic properties including anti-inflammatory effect. In the present study, we analyzed the role of formononetin in acute lung injury induced by lipopolysaccharide (LPS) in mice. The cell counting in the bronchoalveolar lavage fluid (BALF) was measured. The animal lung edema degree was evaluated by wet/dry weight ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity was assayed by SOD and MPO kits, respectively. The levels of inflammatory mediators, tumor necrosis factor-α (TNF-α) and IL-6,were assayed by enzyme-linked immunosorbent assay method. Pathological changes of hung tissues were observed by HE staining. Peroxisome proliferator-activated receptor (PPAR)-γ gene expression was measured by real-time PCR. The data showed that treatment with the formononetin group markedly attenuated inflammatory cell numbers in the BALF, increased PPAR-γ gene expression and improved SOD activity and inhibited MPO activity. The histological changes of the lungs were also significantly improved by formononetin compared to LPS group. The results indicated that formononetin has a protective effect on LPS-induced acute lung injury in mice. PMID:23907652

  8. Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection.

    PubMed

    Erickson, John J; Rogers, Meredith C; Tollefson, Sharon J; Boyd, Kelli L; Williams, John V

    2016-07-01

    Viruses are frequent causes of lower respiratory infection (LRI). Programmed cell death-1 (PD-1) signaling contributes to pulmonary CD8(+) T cell (TCD8) functional impairment during acute viral LRI, but the role of TCD8 impairment in viral clearance and immunopathology is unclear. We now find that human metapneumovirus infection induces virus-specific lung TCD8 that fail to produce effector cytokines or degranulate late postinfection, with minimally increased function even in the absence of PD-1 signaling. Impaired lung TCD8 upregulated multiple inhibitory receptors, including PD-1, lymphocyte activation gene 3 (LAG-3), T cell Ig mucin 3, and 2B4. Moreover, coexpression of these receptors continued to increase even after viral clearance, with most virus-specific lung TCD8 expressing three or more inhibitory receptors on day 14 postinfection. Viral infection also increased expression of inhibitory ligands by both airway epithelial cells and APCs, further establishing an inhibitory environment. In vitro Ab blockade revealed that multiple inhibitory receptors contribute to TCD8 impairment induced by either human metapneumovirus or influenza virus infection. In vivo blockade of T cell Ig mucin 3 signaling failed to enhance TCD8 function or reduce viral titers. However, blockade of LAG-3 in PD-1-deficient mice restored TCD8 effector functions but increased lung pathology, indicating that LAG-3 mediates lung TCD8 impairment in vivo and contributes to protection from immunopathology during viral clearance. These results demonstrate that an orchestrated network of pathways modifies lung TCD8 functionality during viral LRI, with PD-1 and LAG-3 serving prominent roles. Lung TCD8 impairment may prevent immunopathology but also contributes to recurrent lung infections. PMID:27259857

  9. Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9.

    PubMed

    Zhang, Lemeng; Deng, Songyun; Zhao, Shuangping; Ai, Yuhang; Zhang, Lina; Pan, Pinhua; Su, Xiaoli; Tan, Hongyi; Wu, Dongdong

    2016-01-01

    The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1β, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1β, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner. PMID:27589725

  10. Role of Complement C5 in Experimental Blunt Chest Trauma-Induced Septic Acute Lung Injury (ALI)

    PubMed Central

    Karbach, Michael; Braumueller, Sonja; Kellermann, Philipp; Gebhard, Florian; Huber-Lang, Markus; Perl, Mario

    2016-01-01

    Background Severe blunt chest trauma is associated with high mortality. Sepsis represents a serious risk factor for mortality in acute respiratory distress syndrome (ARDS). In septic patients with ARDS complement activation products were found to be elevated in the plasma. In single models like LPS or trauma complement has been studied to some degree, however in clinically highly relevant double hit models such as the one used here little data is available. Here, we hypothesized that absence of C5 is correlated with a decreased inflammatory response in trauma induced septic acute lung injury. Methods 12 hrs after DH in mice the local and systemic cytokines and chemokines were quantified by multiplex bead array or ELISA, activated caspase-3 by western blot. Data were analyzed using one-way ANOVA followed by post-hoc Sidak’s multiple comparison test (significance, p≤ 0.05). Results In lung tissue interleukin (IL)-6, monocyte chemo attractant protein-1 (MCP-1) and granulocyte-colony stimulating factor (G-CSF) was elevated in both C5-/- mice and wildtype littermates (wt), whereas caspase-3 was reduced in lungs after DH in C5-/- mice. Systemically, reduced keratinocyte-derived chemokine (KC) levels were observed after DH in C5-/- compared to wt mice. Locally, lung myeloperoxidase (MPO), protein, IL-6, MCP-1 and G-CSF in brochoalveolar lavage fluid (BALF) were elevated after DH in C5-/- compared to wt. Conclusions In the complex but clinically relevant DH model the local and systemic inflammatory immune response features both, C5-dependent and C5-independent characteristics. Activation of caspase-3 in lung tissue after DH was C5-dependent whereas local inflammation in lung tissue was C5-independent. PMID:27437704

  11. Isoflurane Prevents Acute Lung Injury Through ADP-Mediated Platelet Inhibition

    PubMed Central

    Harr, Jeffrey N.; Moore, Ernest E.; Stringham, John; Wohlauer, Max V.; Fragoso, Miguel; Jones, Wilbert L.; Gamboni, Fabia; Silliman, Christopher C.; Banerjee, Anirban

    2012-01-01

    Background Growing evidence suggests platelets are essential in post-traumatic acute lung injury (ALI). Halogenated ethers interfere with platelet-granulocyte aggregate formation. The potential benefit of halogenated ethers has not been investigated in trauma/hemorrhagic shock (T/HS) models. Therefore, we hypothesized that isoflurane decreases T/HS-mediated ALI through platelet inhibition. Methods Sprauge-Dawley rats (n=47) were anesthetized by either pentobarbital or inhaled isoflurane, and placed into groups: control, trauma (laparotomy) sham shock, T/HS (MAP of 30 mmHg × 45 min), pre-treatment with an ADP receptor antagonist, or T/HS with isoflurane initiated during resuscitation. ALI was determined by BALF protein and pulmonary immunofluorescence. PlateletMapping™ specifically evaluated thrombin-independent inhibition of the ADP and AA pathways of platelet activation. Results Pre-treatment with isoflurane abrogated ALI as measured by both BAL fluid protein and pulmonary immunofluorescence (p<0.001). PlateletMapping™, revealed specific platelet ADP-pathway inhibition with isoflurane (p<0.001). Pre-treatment with an ADP receptor antagonist decreased ALI to sham levels, confirming that specific platelet ADP inhibition decreases ALI. Isoflurane initiated during resuscitation also decreased ALI (p<0.001). Conclusion Isoflurane attenuates ALI through an anti-platelet mechanism, in part, through inhibition of the platelet ADP pathway. Isoflurane given post-injury also protects against ALI, and highlights the potential applications of this therapy in various ischemia/reperfusion clinical scenarios. PMID:22828148

  12. The approach taken to reducing the risk of transfusion related acute lung injury in Canada.

    PubMed

    Growe, G H; Petraszko, T R; Bigham, Mark

    2008-07-01

    Transfusion related acute lung injury (TRALI) has become a major reported cause of severe transfusion reactions and mortality. Over the past four years significant changes have been taken in Canada in order both to improve the recognition of the risk and to decrease its incidence. An international meeting was held in April of 2004 entitled "Towards an Understanding of TRALI". As a result of the analysis and recommendations from this meeting, the Canadian Blood Services established an ongoing review committee and established a laboratory diagnostic facility to identify at risk donors and recipients. A system has been developed to identify implicated donors and exclude them from the blood donor pool. Other steps have been taken to exclude potentially high risk donors, such as previously pregnant females, from the plasma and platelet donor pool. A considerable amount of education also has been offered to clinical services in the country. This paper summarizes the definitions, categorizations of implicated donors, and the ongoing precautionary activities related to plasma products. Noted within the article are the methods used for locating and selecting data. These were primarily based on the international TRALI conference in 2004, and from ongoing discussions and information provided by the Canadian Blood Services TRALI Review Committee. No ethics referral or approval was requested, and a summary is included in the article. PMID:20041083

  13. Screening of multiparous women to avoid transfusion-related acute lung injury: a single centre experience.

    PubMed

    Sachs, U J H; Link, E; Hofmann, C; Wasel, W; Bein, G

    2008-12-01

    The aim of this study was to investigate which approach for serological testing of multiparous donors might be feasible and effective to reduce the risk of transfusion-related acute lung injury (TRALI). TRALI is a serious adverse event of blood transfusion. Antibodies to granulocytes and human leucocyte antigens (HLAs) are frequently detected in sera of implicated donors. These donors are often multiparous women. A general deferral of female plasma or screening strategies for leucocyte antibodies has been proposed to increase blood safety. A prospective study was initiated in 2003. Until 2006, serum samples from all female donors reporting three or more pregnancies (n = 229) were screened for the presence of antibodies against granulocytes and HLAs by immunofluorescence and agglutination tests as well as by a commercial HLA enzyme immunoassay. In total, 40% of all multiparous women were reactive in one of the assays. Twenty-nine percent of the reactive sera contained antibodies to granulocytes but not to HLAs. During the observation period, three TRALI reactions occurred in our hospital, two of which would have been prevented if the screening program had been extended to all previously pregnant donors. We conclude from these data that, not unexpectedly, the number of previous pregnancies is not a reliable indicator for the likelihood of inducing TRALI. More importantly, screening strategies for antibodies that might induce TRALI should probably not be reduced to HLA antibody screening. This finding awaits further research. PMID:19140817

  14. Acute secondary effects in the esophagus in patients undergoing radiotherapy for carcinoma of the lung

    SciTech Connect

    Mascarenhas, F.; Silvestre, M.E.; Sa da Costa, M.; Grima, N.; Campos, C.; Chaves, P.

    1989-02-01

    The incidence and nature of acute secondary irradiation esophagitis was studied in a series of 38 patients undergoing 60Co teletherapy for carcinoma of the lung. Thirty-four patients were male and four female, with ages ranging from 38 to 78 years. The mediastinum being irradiated in the process, all the patients underwent endoscopy for signs of esophagitis and/or gastritis after a dose of 30-40 Gy was delivered to the esophagus. Eighteen patients complained of dysphagia, but only in 12 of them did endoscopy show esophagitis. Of the remaining patients without complaints five had endoscopic signs of esophagitis. Gastritis was found in 18 cases and confirmed histologically in 14. In 17 cases, esophagitis and/or gastritis were confirmed histologically. It is believed that there is a fairly close correlation among clinical, endoscopic, and histological findings to support the claim that esophagitis in these patients is radiation induced. However, the cause of gastritis is not well understood. Data in the literature suggest that nonsteroid anti-inflammatory agents can act as prophylactic means of preventing radiation esophagitis.

  15. Small airway remodeling in acute respiratory distress syndrome: a study in autopsy lung tissue

    PubMed Central

    2011-01-01

    Introduction Airway dysfunction in patients with the Acute Respiratory Distress Syndrome (ARDS) is evidenced by expiratory flow limitation and dynamic hyperinflation. These functional alterations have been attributed to closure/obstruction of small airways. Airway morphological changes have been reported in experimental models of acute lung injury, characterized by epithelial necrosis and denudation in distal airways. To date, however, no study has focused on the morphological airway changes in lungs from human subjects with ARDS. The aim of this study is to evaluate structural and inflammatory changes in distal airways in ARDS patients. Methods We retrospectively studied autopsy lung tissue from subjects who died with ARDS and from control subjects who died of non pulmonary causes. Using image analysis, we quantified the extension of epithelial changes (normal, abnormal and denudated epithelium expressed as percentages of the total epithelium length), bronchiolar inflammation, airway wall thickness, and extracellular matrix (ECM) protein content in distal airways. The Student's t-test or the Mann-Whitney test was used to compare data between the ARDS and control groups. Bonferroni adjustments were used for multiple tests. The association between morphological and clinical data was analyzed by Pearson rank test. Results Thirty-one ARDS patients (A: PaO2/FiO2 ≤200, 45 ± 14 years, 16 males) and 11 controls (C: 52 ± 16 years, 7 males) were included in the study. ARDS airways showed a shorter extension of normal epithelium (A:32.9 ± 27.2%, C:76.7 ± 32.7%, P < 0.001), a larger extension of epithelium denudation (A:52.6 ± 35.2%, C:21.8 ± 32.1%, P < 0.01), increased airway inflammation (A:1(3), C:0(1), P = 0.03), higher airway wall thickness (A:138.7 ± 54.3 μm, C:86.4 ± 33.3 μm, P < 0.01), and higher airway content of collagen I, fibronectin, versican and matrix metalloproteinase-9 (MMP-9) compared to controls (P ≤0.03). The extension of normal epithelium

  16. Acute Kidney Injury in Patients with Acute Lung Injury: Impact of Fluid Accumulation on Classification of Acute Kidney Injury and Associated Outcomes

    PubMed Central

    Liu, Kathleen D.; Thompson, B. Taylor; Ancukiewicz, Marek; Steingrub, Jay S.; Douglas, Ivor S.; Matthay, Michael A.; Wright, Patrick; Peterson, Michael W.; Rock, Peter; Hyzy, Robert C.; Anzueto, Antonio; Truwit, Jonathon D.

    2011-01-01

    Objective It has been suggested that fluid accumulation may delay recognition of acute kidney injury (AKI). We sought to determine the impact of fluid balance on the incidence of non-dialysis requiring AKI in patients with acute lung injury and to describe associated outcomes, including mortality. Design Analysis of the Fluid and Catheter Treatment Trial, a factorial randomized clinical trial of conservative versus liberal fluid management and of management guided by a central venous versus pulmonary artery catheter. Setting and Patients 1000 patients at ARDS Network hospitals. Measurements and Main Results The incidence of AKI, defined as an absolute rise in creatinine of ≥ 0.3 mg/dL or a relative change of > 50% over 48 hours, was examined before and after adjustment of serum creatinine for fluid balance. The incidence of AKI before adjustment for fluid balance was greater in those managed with the conservative fluid protocol (57 versus 51%, p = 0.04). After adjustment for fluid balance, the incidence of AKI was greater in those managed with the liberal fluid protocol (66 versus 58%, p = 0.007). Patients who met AKI criteria after adjustment of creatinine for fluid balance (but not before) had a mortality rate that was significantly greater than those who did not meet AKI criteria both before and after adjustment for fluid balance (31 versus 12%, p < 0.001) and those who had AKI before but not after adjustment for fluid balance (31 versus 11%, p = 0.005). The mortality of those patients meeting AKI criteria after but not before adjustment for fluid balance was similar to patients with AKI both before and after adjustment for fluid balance (31% versus 38%, p = 0.18). Conclusions Fluid management influences serum creatinine and therefore the diagnosis of AKI using creatinine-based definitions. Patients with “unrecognized” AKI that is identified after adjusting for positive fluid balance have high mortality rates, and patients who have AKI before but not after

  17. Immunological and Inflammatory Responses to Organic Dust in Agriculture

    PubMed Central

    Poole, Jill A.; Romberger, Debra J.

    2012-01-01

    Purpose of review Agriculture represents a major industry worldwide, and despite protection against the development of IgE-mediated diseases, chronic exposure to agriculture-related organic dusts is associated with an increased risk of developing respiratory disease. This article will review the literature regarding new knowledge of important etiologic agents in the dusts and focus on the immunologic responses following acute and repetitive organic dust exposures. Recent findings Although endotoxin remains important, there is an emerging role for non-endotoxin components such as peptidoglycans from Gram-positive bacteria. Pattern recognition receptors including Toll-like receptor 4 (TLR4), TLR2 and intracellular nucleotide oligomerization domain-like receptors are partially responsible for mediating the inflammatory consequences. Repeated organic dust exposures modulate innate and adaptive immune function with a resultant adaptation-like response. However, repetitive exposures cause lung parenchymal inflammation, chronic disease, and lung function decline over time. Summary The immunological consequences of organic dust exposure in the farming industry are likely explained by the diversity of microbial motifs in dust that can elicit differing innate immune receptor signaling pathways. Whereas initial activation results in a robust inflammatory response, repetitive dust exposures modulate immunity. This can result in low-grade, chronic inflammation and/or protection against allergic disease. PMID:22306554

  18. Anti‑inflammatory effects of Panax notoginseng saponins ameliorate acute lung injury induced by oleic acid and lipopolysaccharide in rats.

    PubMed

    Chen, Yu-Qing; Rong, Ling; Qiao, Jian-Ou

    2014-09-01

    This study investigated the effect of Panax notoginseng saponins (PNS) on acute lung injury (ALI) induced by oleic acid (OA) and lipopolysaccharide (LPS). A total of 28 Wistar rats were divided into four groups: sham; sham + PNS; OA‑LPS‑induced ALI and ALI + PNS. Lung tissue histology, lung wet‑to‑dry (W/D) weight ratio, extravascular lung water (EVLW) and epithelial sodium channel α (αENaC) mRNA and protein expression were examined. In addition, levels of inflammatory cytokines, including tumor necrosis factor α (TNF‑α), interleukin (IL)‑6 and IL‑10, as well as total leukocyte and neutrophil counts, were analyzed in rat bronchoalveolar lavage fluid (BALF) and serum. ALI + PNS rats were observed to exhibit significantly lower pulmonary parenchymal damage and EVLW compared with ALI rats. Furthermore, total leukocyte and neutrophil counts, and levels of inflammatory cytokines were significantly decreased following PNS administration in ALI rats. In addition, the decrease in αENaC mRNA and protein expression observed in the lung tissue of ALI rats was partially restored following PNS treatment. PNS treatment was demonstrated to ameliorate OA‑LPS‑induced ALI, potentially through restoration of αENaC mRNA and protein expression and through PNS‑induced anti‑inflammatory effects. PMID:24938646

  19. Low levels of tissue factor lead to alveolar hemorrhage, potentiating murine acute lung injury and oxidative stress

    PubMed Central

    Bastarache, J.A.; Sebag, S. C.; Clune, J.K.; Grove, B.S.; Lawson, W.E.; Janz, D. R.; Roberts, L. J.; Dworski, R; Mackman, N.; Ware, L. B.

    2013-01-01

    Background Systemic blockade of Tissue Factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown. Hypothesis We used mice with complete knockout of mouse TF and low levels (~1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury. Methods LTF mice were treated with 10 μg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal (IT) injection and studied at 24 hours. Results Contrary to our hypothesis, LTF mice had increased lung inflammation and injury as measured by bronchoalveolar lavage cell count (3.4 × 105 WT LPS versus 3.3 × 105 LTF LPS, p=0.947) and protein (493 μg/ml WT LPS versus 1014 μg/ml LTF LPS, p=0.006), proinflammatory cytokines (TNF-α, IL-10, IL-12, p<0.035 WT LPS versus LTF LPS) and histology compared to wild type mice. LTF mice also had increased hemorrhage and free hemoglobin in the airspace accompanied by increased oxidant stress as measured by lipid peroxidation products (F2-Isoprostanes and Isofurans). Conclusions These findings indicate that global TF deficiency does not confer protection in a direct lung injury model. Rather, TF deficiency causes increased intra-alveolar hemorrhage following LPS leading to increased lipid peroxidation. Strategies to globally inhibit tissue factor may be deleterious in patients with ALI. PMID:23033361

  20. Effects of short-term propofol and dexmedetomidine on pulmonary morphofunction and biological markers in experimental mild acute lung injury.

    PubMed

    Cavalcanti, Vinícius; Santos, Cintia Lourenço; Samary, Cynthia Santos; Araújo, Mariana Neves; Heil, Luciana Boavista Barros; Morales, Marcelo Marcos; Silva, Pedro Leme; Pelosi, Paolo; Fernandes, Fatima Carneiro; Villela, Nivaldo; Rocco, Patricia Rieken Macedo

    2014-11-01

    We evaluated whether the short-term use of dexmedetomidine and propofol may attenuate inflammatory response and improve lung morphofunction in experimental acute lung injury (ALI). Thirty-six Wistar rats were randomly divided into five groups. Control (C) and ALI animals received sterile saline solution and Escherichia coli lipopolysaccharide by intraperitoneal injection respectively. After 24h, ALI animals were randomly treated with dexmedetomidine, propofol, or thiopental sodium for 1h. Propofol reduced static lung elastance and resistive pressure and was associated with less alveolar collapse compared to thiopental sodium and dexmedetomidine. Dexmedetomidine improved oxygenation, but did not modify lung mechanics or histology. Propofol was associated with lower IL (interleukin)-6 and IL-1β expression, whereas dexmedetomidine led to reduced inducible nitric oxide (iNOS) and increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression in lung tissue compared to thiopental sodium. In conclusion, in this model of mild ALI, short-term use of dexmedetomidine and propofol led to different functional effects and activation of biological markers associated with pulmonary inflammation. PMID:25149586

  1. Therapeutic Effect of Intravenous Infusion of Perfluorocarbon Emulsion on LPS-Induced Acute Lung Injury in Rats

    PubMed Central

    Lv, Qi; Yin, Xiaofeng; Song, Jianqi; Landén, Ning Xu; Fan, Haojun

    2014-01-01

    Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) are the leading causes of death in critical care. Despite extensive efforts in research and clinical medicine, mortality remains high in these diseases. Perfluorocarbon (PFC), a chemical compound known as liquid ventilation medium, is capable of dissolving large amounts of physiologically important gases (mainly oxygen and carbon dioxide). In this study we aimed to investigate the effect of intravenous infusion of PFC emulsion on lipopolysaccharide (LPS) induced ALI in rats and elucidate its mechanism of action. Forty two Wistar rats were randomly divided into three groups: 6 rats were treated with saline solution by intratracheal instillation (control group), 18 rats were treated with LPS by intratracheal instillation (LPS group) and the other 18 rats received PFC through femoral vein prior to LPS instillation (LPS+PFC group). The rats in the control group were sacrificed 6 hours later after saline instillation. At 2, 4 and 6 hours of exposure to LPS, 6 rats in the LPS group and 6 rats in LPS+PFC group were sacrificed at each time point. By analyzing pulmonary pathology, partial pressure of oxygen in the blood (PaO2) and lung wet-dry weight ratio (W/D) of each rat, we found that intravenous infusion of PFC significantly alleviated acute lung injury induced by LPS. Moreover, we showed that the expression of pulmonary myeloperoxidase (MPO), intercellular adhesion molecule-1 (ICAM-1) of endothelial cells and CD11b of polymorphonuclear neutrophils (PMN) induced by LPS were significantly decreased by PFC treatment in vivo. Our results indicate that intravenous infusion of PFC inhibits the infiltration of PMNs into lung tissue, which has been shown as the core pathogenesis of ALI/ARDS. Thus, our study provides a theoretical foundation for using intravenous infusion of PFC to prevent and treat ALI/ARDS in clinical practice. PMID:24489970

  2. Therapeutic effect of intravenous infusion of perfluorocarbon emulsion on LPS-induced acute lung injury in rats.

    PubMed

    Hou, Shike; Ding, Hui; Lv, Qi; Yin, Xiaofeng; Song, Jianqi; Landén, Ning Xu; Fan, Haojun

    2014-01-01

    Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) are the leading causes of death in critical care. Despite extensive efforts in research and clinical medicine, mortality remains high in these diseases. Perfluorocarbon (PFC), a chemical compound known as liquid ventilation medium, is capable of dissolving large amounts of physiologically important gases (mainly oxygen and carbon dioxide). In this study we aimed to investigate the effect of intravenous infusion of PFC emulsion on lipopolysaccharide (LPS) induced ALI in rats and elucidate its mechanism of action. Forty two Wistar rats were randomly divided into three groups: 6 rats were treated with saline solution by intratracheal instillation (control group), 18 rats were treated with LPS by intratracheal instillation (LPS group) and the other 18 rats received PFC through femoral vein prior to LPS instillation (LPS+PFC group). The rats in the control group were sacrificed 6 hours later after saline instillation. At 2, 4 and 6 hours of exposure to LPS, 6 rats in the LPS group and 6 rats in LPS+PFC group were sacrificed at each time point. By analyzing pulmonary pathology, partial pressure of oxygen in the blood (PaO2) and lung wet-dry weight ratio (W/D) of each rat, we found that intravenous infusion of PFC significantly alleviated acute lung injury induced by LPS. Moreover, we showed that the expression of pulmonary myeloperoxidase (MPO), intercellular adhesion molecule-1 (ICAM-1) of endothelial cells and CD11b of polymorphonuclear neutrophils (PMN) induced by LPS were significantly decreased by PFC treatment in vivo. Our results indicate that intravenous infusion of PFC inhibits the infiltration of PMNs into lung tissue, which has been shown as the core pathogenesis of ALI/ARDS. Thus, our study provides a theoretical foundation for using intravenous infusion of PFC to prevent and treat ALI/ARDS in clinical practice. PMID:24489970

  3. Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo.

    PubMed

    Chan, Michael C W; Kuok, Denise I T; Leung, Connie Y H; Hui, Kenrie P Y; Valkenburg, Sophie A; Lau, Eric H Y; Nicholls, John M; Fang, Xiaohui; Guan, Yi; Lee, Jae W; Chan, Renee W Y; Webster, Robert G; Matthay, Michael A; Peiris, J S Malik

    2016-03-29

    Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium's protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation. PMID:26976597

  4. Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

    PubMed Central

    Chan, Michael C. W.; Kuok, Denise I. T.; Leung, Connie Y. H.; Hui, Kenrie P. Y.; Valkenburg, Sophie A.; Lau, Eric H. Y.; Nicholls, John M.; Fang, Xiaohui; Guan, Yi; Lee, Jae W.; Chan, Renee W. Y.; Webster, Robert G.; Matthay, Michael A.; Peiris, J. S. Malik

    2016-01-01

    Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium’s protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation. PMID:26976597

  5. Low molecular weight heparin prevents CLP-induced acute lung injury in rats by anti-inflammatory coagulation.

    PubMed

    Lu, Xiao; Zhao, Liang; Xu, Yong-Hua

    2013-02-01

    The aim of our study was to observe the influence of low molecular Weight heparin (LMWH) on systemic inflammation, including high mobility group box 1 protein (HMGB1) and protective effect on acute lung injury induced by cecal ligation and puncture(CLP). Discuss the mechanism of this effect. 144 male SD rats were randomly divided into sham operation group (A), normal treatment group (B), the LMWH treatment group (C), n=48.Group A received a sham operation and the other groups were underwent CLP operation. Groups A and B accepted intraperitoneal injection (i.p.) of normal saline (NS) at a dose of 2.0 ml/kg and ceftriaxone (30 mg/kg), Group C were intraperitoneal injection additional LMWH (150 U/kg) except saline and ceftriaxone. Observe points were made at 3, 6, 12, 18, 24, 48 h, the rats were anesthetized and killed, mortality, lungs wet/dry ratio and Pathology change were determined. HMGB-1 mRNA, protein of lung tissues was calculated by RT-PCR and Western blot. TNF-α and IL-6 of blood plasma calculated by ELSIA. There was significantly different in each index between A and B group (p<0.05).Compared with CLP group, there was a significant decrease in the lung injury, the mortality, HMGB1 mRNA and protein expression on lung tissues (p<0.05). LMWH can decreases cytokine, HMGB1 levels of lung tissue during CLP-induced inflammation. As a result, LMWH ameliorated lung pathology and reduces mortality in CLP-induced systemic inflammation in a rat model. This effect may be mediated through the inhibition of axis of inflammation and coagulation. PMID:23448611

  6. Blocking Cyclic Adenosine Diphosphate Ribose-mediated Calcium Overload Attenuates Sepsis-induced Acute Lung Injury in Rats

    PubMed Central

    Peng, Qian-Yi; Zou, Yu; Zhang, Li-Na; Ai, Mei-Lin; Liu, Wei; Ai, Yu-Hang

    2016-01-01

    Background: Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality. Intracellular Ca2+ overload plays an important role in the pathophysiology of sepsis-induced ALI, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALI is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALI and whether blocking cADPR-mediated calcium overload attenuates ALI. Methods: Septic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-α, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured. Results: NAD+, cADPR, CD38, and intracellular Ca2+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-α and MDA levels (P < 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats. Conclusions: The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALI. PMID:27411462

  7. Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury.

    PubMed

    Natarajan, Viswanathan; Dudek, Steven M; Jacobson, Jeffrey R; Moreno-Vinasco, Liliana; Huang, Long Shuang; Abassi, Taimur; Mathew, Biji; Zhao, Yutong; Wang, Lichun; Bittman, Robert; Weichselbaum, Ralph; Berdyshev, Evgeny; Garcia, Joe G N

    2013-07-01

    Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P1-5 as well as intracellularly on various targets. S1P-mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and others have demonstrated that S1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI. PMID:23449739

  8. Prostacyclin post-treatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1

    PubMed Central

    Birukova, Anna A.; Meng, Fanyong; Tian, Yufeng; Meliton, Angelo; Sarich, Nicolene; Quilliam, Lawrence A.; Birukov, Konstantin G.

    2015-01-01

    Protective effects of prostacyclin (PC) or its stable analog beraprost against agonist-induced lung vascular inflammation have been associated with elevation of intracellular cAMP and Rac GTPase signaling which inhibited the RhoA GTPase-dependent pathway of endothelial barrier dysfunction. This study investigated a distinct mechanism of PC-stimulated lung vascular endothelial (EC) barrier recovery and resolution of LPS-induced inflammation mediated by small GTPase Rap1. Efficient barrier recovery was observed in LPS-challenged pulmonary EC after prostacyslin administration even after 15 hrs of initial inflammatory insult and was accompanied by the significant attenuation of p38 MAP kinase and NFkB signaling and decreased production of IL-8 and soluble ICAM1. These effects were reproduced in cells post-treated with 8CPT, a small molecule activator of Rap1-specific nucleotide exchange factor Epac. By contrast, pharmacologic Epac inhibitor, Rap1 knockdown, or knockdown of cell junction-associated Rap1 effector afadin attenuated EC recovery caused by PC or 8CPT post-treatment. The key role of Rap1 in lung barrier restoration was further confirmed in the murine model of LPS-induced acute lung injury. Lung injury was monitored by measurements of bronchoalveolar lavage protein content, cell count, and Evans blue extravasation and live imaging of vascular leak over 6 days using a fluorescent tracer. The data showed significant acceleration of lung recovery by PC and 8CPT post-treatment, which was abrogated in Rap1a−/− mice. These results suggest that post-treatment with PC triggers the Epac/Rap1/afadin-dependent mechanism of endothelial barrier restoration and downregulation of p38MAPK and NFkB inflammatory cascades, altogether leading to accelerated lung recovery. PMID:25545047

  9. Summary of the 2014 Alcohol and Immunology Research Interest Group (AIRIG) meeting.

    PubMed

    Hammer, Adam M; Morris, Niya L; Cannon, Abigail R; Shults, Jill A; Curtis, Brenda; Casey, Carol A; Sueblinvong, Viranuj; Persidsky, Yuri; Nixon, Kimberly; Brown, Lou Ann; Waldschmidt, Thomas; Mandrekar, Pranoti; Kovacs, Elizabeth J; Choudhry, Mashkoor A

    2015-12-01

    On November 21, 2014 the 19th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at Loyola University Chicago Health Sciences Campus in Maywood, Illinois. The meeting focused broadly on inflammatory cell signaling responses in the context of alcohol and alcohol-use disorders, and was divided into four plenary sessions focusing on the gut and liver, lung infections, general systemic effects of alcohol, and neuro-inflammation. One common theme among many talks was the differential roles of macrophages following both chronic and acute alcohol intoxication. Macrophages were shown to play significant roles in regulating inflammation, oxidative stress, and viral infection following alcohol exposure in the liver, lungs, adipose tissue, and brain. Other work examined the role of alcohol on disease progression in a variety of pathologies including psoriasis, advanced stage lung disease, and cancer. PMID:26520175

  10. Hepatocytes as Immunological Agents.

    PubMed

    Crispe, Ian N

    2016-01-01

    Hepatocytes are targeted for infection by a number of major human pathogens, including hepatitis B virus, hepatitis C virus, and malaria. However, hepatocytes are also immunological agents in their own right. In systemic immunity, they are central in the acute-phase response, which floods the circulation with defensive proteins during diverse stresses, including ischemia, physical trauma, and sepsis. Hepatocytes express a variety of innate immune receptors and, when challenged with pathogen- or damage-associated molecular patterns, can deliver cell-autonomous innate immune responses that may result in host defense or in immunopathology. Important human pathogens have evolved mechanisms to subvert these responses. Finally, hepatocytes talk directly to T cells, resulting in a bias toward immune tolerance. PMID:26685314

  11. The Vascular Endothelial Growth Factors-Expressing Character of Mesenchymal Stem Cells Plays a Positive Role in Treatment of Acute Lung Injury In Vivo

    PubMed Central

    Yang, Yi; Hu, Shuling; Xu, Xiuping; Li, Jinze; Liu, Airan; Han, Jibin; Liu, Songqiao; Liu, Ling; Qiu, Haibo

    2016-01-01

    Recently, mesenchymal stem cells (MSC) have been proved to be beneficial in acute respiratory distress syndrome (ARDS). Vascular endothelial growth factor (VEGF) is an important angiogenesis factor that MSC release. However, the precise role of VEGF-expressing character of MSC in the MSC treatment for ARDS remains obscure. Here, we firstly knocked down the gene VEGF in MSC (MSC-ShVEGF) with lentiviral transduction. Then we injected the MSC-ShVEGF to rats with lipopolysaccharide-induced acute lung injury (ALI) via the tail vein. Data showed that MSC transplantation significantly increased VEGF levels in the lung, reduced lung permeability, protected lung endothelium from apoptosis, facilitated VE-cadherin recovery, controlled inflammation, and attenuated lung injury. However, VEGF gene knockdown in MSC led to relatively insufficient VEGF expression in the injured lung and significantly diminished the therapeutic effects of MSC on ALI, suggesting an important role of VEGF-expressing behavior of MSC in the maintenance of VEGF in the lung and the MSC treatment for ALI. Hence, we conclude that MSC restores the lung permeability and attenuates lung injury in rats with ALI in part by maintaining a “sufficient” VEGF level in the lung and the VEGF-expressing character of MSC plays a positive role in the therapeutic effects of MSC on ARDS. PMID:27313398

  12. A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury

    PubMed Central

    Dib, Marwan; Zsengeller, Zsuzsanna; Mitsialis, Alex; Lu, Bao; Craig, Stewart; Gerard, Norma P.

    2009-01-01

    The neuropeptide substance P manifests its biological functions through ligation of a G protein-coupled receptor, the NK1R. Mice with targeted deletion of this receptor reveal a preponderance of proinflammatory properties resulting from ligand activation, demonstrating a neurogenic component to multiple forms of inflammation and injury. We hypothesized that NK1R deficiency would afford a similar protection from inflammation associated with hyperoxia. Counter to our expectations, however, NK1R−/− animals suffered significantly worse lung injury compared with wild-type mice following exposure to 90% oxygen. Median survival was shortened to 84 h for NK1R−/− mice from 120 h for wild-type animals. Infiltration of inflammatory cells into the lungs was significantly increased; NK1R−/− animals also exhibited increased pulmonary edema, hemorrhage, and bronchoalveolar lavage fluid protein levels. TdT-mediated dUTP nick end labeling (TUNEL) staining was significantly elevated in NK1R−/− animals following hyperoxia. Furthermore, induction of metallothionein and Na+-K+-ATPase was accelerated in NK1R−/− compared with wild-type mice, consistent with increased oxidative injury and edema. In cultured mouse lung epithelial cells in 95% O2, however, addition of substance P promoted cell death, suggesting the neurogenic component of hyperoxic lung injury is mediated by additional mechanisms in vivo. Release of bioactive constituents including substance P from sensory neurons results from activation of the vanilloid receptor, TRPV1. In mice with targeted deletion of the TRPV1 gene, acute hyperoxic injury is attenuated relative to NK1R−/− animals. Our findings thus reveal a major neurogenic mechanism in acute hyperoxic lung injury and demonstrate concerted actions of sensory neurotransmitters revealing significant protection for NK1R-mediated functions. PMID:19633070

  13. β-Nicotinamide adenine dinucleotide attenuates lipopolysaccharide-induced inflammatory effects in a murine model of acute lung injury.

    PubMed

    Umapathy, Nagavedi Siddaramappa; Gonzales, Joyce; Fulzele, Sadanand; Kim, Kyung-mi; Lucas, Rudolf; Verin, Alexander Dimitrievich

    2012-06-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) occur in approximately 200,000 patients per year. Studies indicate that lung endothelium plays a significant role in ALI. The authors' recent in vitro studies demonstrate a novel mechanism of β-nicotinamide adenine dinucleotide (β-NAD)-induced protection against gram-positive (pneumolysin, PLY) and gram-negative (lipopolysaccharide, LPS) toxin-induced lung endothelial cell (EC) barrier dysfunction. The objective of the current study was to evaluate the protective effect of β-NAD against LPS-induced ALI in mice. C57BL/6J mice were randomly divided into 4 groups: vehicle, β-NAD, LPS, and LPS/β-NAD. After surgery, mice were allowed to recover for 24 hours. Evans blue dye-albumin (EBA) was given through the internal jugular vein 2 hours prior to the termination of the experiments. Upon sacrificing the animals, bronchoalveolar lavage fluid (BALF) was collected and the lungs were harvested. β-NAD treatment significantly attenuated the inflammatory response by means of reducing the accumulation of cells and protein in BALF, blunting the parenchymal neutrophil infiltration, and preventing capillary leak. In addition, the histological examination demonstrated decreased interstitial edema in the LPS/β-NAD specimens, as compared to the LPS-only specimens. The mRNA levels of the anti-inflammatory cytokines were up-regulated in the LPS group treated with β-NAD compared to the LPS-only-treated group. β-NAD treatment down-regulated the mRNA levels of the proinflammatory cytokines. These findings suggest that β-NAD could be investigated as a therapeutic option against bacterial toxin-induced lung inflammation and ALI in mice. PMID:22563684

  14. Cooperation between Monocyte-Derived Cells and Lymphoid Cells in the Acute Response to a Bacterial Lung Pathogen

    PubMed Central

    Brown, Andrew S.; Yang, Chao; Fung, Ka Yee; Bachem, Annabell; Bourges, Dorothée; Bedoui, Sammy; Hartland, Elizabeth L.; van Driel, Ian R.

    2016-01-01

    Legionella pneumophila is the causative agent of Legionnaires’ disease, a potentially fatal lung infection. Alveolar macrophages support intracellular replication of L. pneumophila, however the contributions of other immune cell types to bacterial killing during infection are unclear. Here, we used recently described methods to characterise the major inflammatory cells in lung after acute respiratory infection of mice with L. pneumophila. We observed that the numbers of alveolar macrophages rapidly decreased after infection coincident with a rapid infiltration of the lung by monocyte-derived cells (MC), which, together with neutrophils, became the dominant inflammatory cells associated with the bacteria. Using mice in which the ability of MC to infiltrate tissues is impaired it was found that MC were required for bacterial clearance and were the major source of IL12. IL12 was needed to induce IFNγ production by lymphoid cells including NK cells, memory T cells, NKT cells and γδ T cells. Memory T cells that produced IFNγ appeared to be circulating effector/memory T cells that infiltrated the lung after infection. IFNγ production by memory T cells was stimulated in an antigen-independent fashion and could effectively clear bacteria from the lung indicating that memory T cells are an important contributor to innate bacterial defence. We also determined that a major function of IFNγ was to stimulate bactericidal activity of MC. On the other hand, neutrophils did not require IFNγ to kill bacteria and alveolar macrophages remained poorly bactericidal even in the presence of IFNγ. This work has revealed a cooperative innate immune circuit between lymphoid cells and MC that combats acute L. pneumophila infection and defines a specific role for IFNγ in anti-bacterial immunity. PMID:27300652

  15. Inducible expression of indoleamine 2,3-dioxygenase attenuates acute rejection of tissue-engineered lung allografts in rats.

    PubMed

    Ebrahimi, Ammar; Kardar, Gholam Ali; Teimoori-Toolabi, Ladan; Toolabi, LadanTeimoori; Ghanbari, Hossein; Sadroddiny, Esmaeil

    2016-01-15

    Lung disease remains one of the principal causes of death worldwide and the incidence of pulmonary diseases is increasing. Complexity in treatments and shortage of donors leads us to develop new ways for lung disease treatment. One promising strategy is preparing engineered lung for transplantation. In this context, employing new immunosuppression strategies which suppresses immune system locally rather than systemic improves transplant survival. This tends to reduce the difficulties in transplant rejection and the systemic impact of the use of immunosuppressive drugs which causes side effects such as serious infections and malignancies. In our study examining the immunosuppressive effects of IDO expression, we produced rat lung tissues with the help of decellularized tissue, differentiating medium and rat mesenchymal stem cells. Transduction of these cells by IDO expressing lentiviruses provided inducible and local expression of this gene. To examine immunosuppressive properties of IDO expression by these tissues, we transplanted these allografts into rats and, subsequently, evaluated cytokine expression and histopathological properties. Expression of inflammatory cytokines IFNγ and TNFα were significantly downregulated in IDO expressing allograft. Moreover, acute rejection score of this experimental group was also lower comparing other two groups and mRNA levels of FOXP3, a regulatory T cell marker, upregulated in IDO expressing group. However, infiltrating lymphocyte counting did not show significant difference between groups. This study demonstrates that IDO gene transfer into engineered lung allograft tissues significantly attenuates acute allograft damage suggesting local therapy with IDO as a strategy to reduce the need for systemic immunosuppression and, thereby, its side effects. PMID:26506443

  16. Daidzein attenuates lipopolysaccharide-induced acute lung injury via toll-like receptor 4/NF-kappaB pathway.

    PubMed

    Feng, Guang; Sun, Bo; Li, Tian-zuo

    2015-06-01

    Daidzein, a diphenolic isoflavone from many plants and herbs, has been reported to have anti-inflammatory properties. However, the effects of daidzein on lipopolysaccharide (LPS)-induced acute lung injury have not been determined. The aim of this study was to detect the effects of daidzein on LPS-induced acute lung injury and investigate the molecular mechanisms. Daidzein was intraperitoneally injected (2, 4, 8 mg/kg) 30 min after intratracheal instillation of LPS (5 mg/kg) in rats. The results showed that daidzein treatment remarkably improved the pulmonary histology and decreased the lung wet/dry weight ratios. We also found that daidzein significantly inhibited LPS-induced increases of macrophages and neutrophils infiltration of lung tissues, as well as markedly attenuated MPO activity. Moreover, daidzein effectively reduced the inflammatory cytokines release and total protein in bronchoalveolar lavage fluids (BALF). Furthermore, daidzein significantly inhibited LPS-induced toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) protein up-expressions and NF-κB activation in lung tissues. In vitro, daidzein obviously inhibited the expressions of TLR4 and MyD88 and the activation of NF-κB in LPS-stimulated A549 alveolar epithelial cells. In conclusion, these data indicate that the anti-inflammatory effects of daidzein against LPS-induced ALI may be due to its ability to inhibit TLR4-MyD88-NF-κB pathway and daidzein may be a potential therapeutic agent for LPS-induced ALI. PMID:25887269

  17. A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice.

    PubMed

    Eckle, Tobias; Grenz, Almut; Laucher, Stefanie; Eltzschig, Holger K

    2008-10-01

    Although acute lung injury contributes significantly to critical illness, resolution often occurs spontaneously via activation of incompletely understood pathways. We recently found that mechanical ventilation of mice increases the level of pulmonary adenosine, and that mice deficient for extracellular adenosine generation show increased pulmonary edema and inflammation after ventilator-induced lung injury (VILI). Here, we profiled the response to VILI in mice with genetic deletions of each of the 4 adenosine receptors (ARs) and found that deletion of the A2BAR gene was specifically associated with reduced survival time and increased pulmonary albumin leakage after injury. In WT mice, treatment with an A2BAR-selective antagonist resulted in enhanced pulmonary inflammation, edema, and attenuated gas exchange, while an A2BAR agonist attenuated VILI. In bone marrow-chimeric A2BAR mice, although the pulmonary inflammatory response involved A2BAR signaling from bone marrow-derived cells, A2BARs located on the lung tissue attenuated VILI-induced albumin leakage and pulmonary edema. Furthermore, measurement of alveolar fluid clearance (AFC) demonstrated that A2BAR signaling enhanced amiloride-sensitive fluid transport and elevation of pulmonary cAMP levels following VILI, suggesting that A2BAR agonist treatment protects by drying out the lungs. Similar enhancement of pulmonary cAMP and AFC were also observed after beta-adrenergic stimulation, a pathway known to promote AFC. Taken together, these studies reveal a role for A2BAR signaling in attenuating VILI and implicate this receptor as a potential therapeutic target during acute lung injury. PMID:18787641

  18. Study protocol: The Improving Care of Acute Lung Injury Patients (ICAP) study

    PubMed Central

    Needham, Dale M; Dennison, Cheryl R; Dowdy, David W; Mendez-Tellez, Pedro A; Ciesla, Nancy; Desai, Sanjay V; Sevransky, Jonathan; Shanholtz, Carl; Scharfstein, Daniel; Herridge, Margaret S; Pronovost, Peter J

    2006-01-01

    Introduction The short-term mortality benefit of lower tidal volume ventilation (LTVV) for patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has been demonstrated in a large, multi-center randomized trial. However, the impact of LTVV and other critical care therapies on the longer-term outcomes of ALI/ARDS survivors remains uncertain. The Improving Care of ALI Patients (ICAP) study is a multi-site, prospective cohort study that aims to evaluate the longer-term outcomes of ALI/ARDS survivors with a particular focus on the effect of LTVV and other critical care therapies. Methods Consecutive mechanically ventilated ALI/ARDS patients from 11 intensive care units (ICUs) at four hospitals in the city of Baltimore, MD, USA, will be enrolled in a prospective cohort study. Exposures (patient-based, clinical management, and ICU organizational) will be comprehensively collected both at baseline and throughout patients' ICU stay. Outcomes, including mortality, organ impairment, functional status, and quality of life, will be assessed with the use of standardized surveys and testing at 3, 6, 12, and 24 months after ALI/ARDS diagnosis. A multi-faceted retention strategy will be used to minimize participant loss to follow-up. Results On the basis of the historical incidence of ALI/ARDS at the study sites, we expect to enroll 520 patients over two years. This projected sample size is more than double that of any published study of long-term outcomes in ALI/ARDS survivors, providing 86% power to detect a relative mortality hazard of 0.70 in patients receiving higher versus lower exposure to LTVV. The projected sample size also provides sufficient power to evaluate the association between a variety of other exposure and outcome variables, including quality of life. Conclusion The ICAP study is a novel, prospective cohort study that will build on previous critical care research to improve our understanding of the longer-term impact of ALI/ARDS, LTVV and

  19. Regulation and repair of the alveolar-capillary barrier in acute lung injury.

    PubMed

    Bhattacharya, Jahar; Matthay, Michael A

    2013-01-01

    Considerable progress has been made in understanding the basic mechanisms that regulate fluid and protein exchange across the endothelial and epithelial barriers of the lung under both normal and pathological conditions. Clinically relevant lung injury occurs most commonly from severe viral and bacterial infections, aspiration syndromes, and severe shock. The mechanisms of lung injury have been identified in both experimental and clinical studies. Recovery from lung injury requires the reestablishment of an intact endothelial barrier and a functional alveolar epithelial barrier capable of secreting surfactant and removing alveolar edema fluid. Repair mechanisms include the participation of endogenous progenitor cells in strategically located niches in the lung. Novel treatment strategies include the possibility of cell-based therapy that may reduce the severity of lung injury and enhance lung repair. PMID:23398155

  20. Risk Factors for Physical Impairment after Acute Lung Injury in a National, Multicenter Study

    PubMed Central

    Wozniak, Amy W.; Hough, Catherine L.; Morris, Peter E.; Dinglas, Victor D.; Jackson, James C.; Mendez-Tellez, Pedro A.; Shanholtz, Carl; Ely, E. Wesley; Colantuoni, Elizabeth

    2014-01-01

    Rationale: Existing studies of risk factors for physical impairments in acute lung injury (ALI) survivors were potentially limited by single-center design or relatively small sample size. Objectives: To evaluate risk factors for three measures of physical impairments commonly experienced by survivors of ALI in the first year after hospitalization. Methods: A prospective, longitudinal study of 6- and 12-month physical outcomes (muscle strength, 6-minute-walk distance, and Short Form [SF]-36 Physical Function score) for 203 survivors of ALI enrolled from 12 hospitals participating in the ARDS Network randomized trials. Multivariable regression analyses evaluated the independent association of critical illness–related variables and intensive care interventions with impairments in each physical outcome measure, after adjusting for patient demographics, comorbidities, and baseline functional status. Measurements and Main Results: At 6 and 12 months, respectively, mean (± SD) values for strength (presented as proportion of maximum strength score evaluated using manual muscle testing) was 92% (± 8%) and 93% (± 9%), 6-minute-walk distance (as percent-predicted) was 64% (± 22%) and 67% (± 26%), and SF-36 Physical Function score (as percent-predicted) was 61% (± 36%) and 67% (± 37%). After accounting for patient baseline status, there was significant association and statistical interaction of mean daily dose of corticosteroids and intensive care unit length of stay with impairments in physical outcomes. Conclusions: Patients had substantial impairments, from predicted values, for 6-minute-walk distance and SF-36 Physical Function outcome measures. Minimizing corticosteroid dose and implementing existing evidence-based methods to reduce duration of intensive care unit stay and associated patient immobilization may be important interventions for improving ALI survivors’ physical outcomes. PMID:24716641

  1. Mechanisms of transfusion-related acute lung injury (TRALI): anti-leukocyte antibodies.

    PubMed

    Curtis, Brian R; McFarland, Janice G

    2006-05-01

    There is abundant evidence that leukocyte antibodies in blood donor products are somehow involved in transfusion-related acute lung injury (TRALI). Human leukocyte antigen (HLA) class I, HLA class II, and neutrophil-specific antibodies in the plasma of both blood donors and recipients have been implicated in the pathogenesis of TRALI. The case for a relationship between leukocyte antibodies and TRALI is more compelling if concordance between the antigen specificity of the leukocyte antibodies in the donor plasma and the corresponding antigen on the cells of the affected recipient is demonstrated. Such antibody-antigen concordance can be investigated by typing the recipient for the cognate leukocyte antigens or by cross-matching the donor plasma against the recipient's leukocytes. Two proposed pathophysiologic mechanisms for TRALI have received the most attention: the antibody hypothesis and the two-event hypothesis. The final common pathway in all of the proposed pathogenic mechanisms of TRALI is increased pulmonary capillary permeability, which results in movement of plasma into the alveolar space causing pulmonary edema. A typical TRALI serologic workup consists of tests for HLA class I and II and neutrophil-specific antibodies. The use of flow cytometry and HLA-coated microbeads is recommended for detection of HLA antibodies in plasma of implicated blood donors and a combination of the granulocyte agglutination test and granulocyte immunofluorescence test for detection of neutrophil-specific antibodies. Genotyping for class I and II HLA and for a limited number of neutrophil antigens may also be helpful in establishing antibody-antigen concordance. PMID:16617255

  2. HIF2α signaling inhibits adherens junctional disruption in acute lung injury

    PubMed Central

    Gong, Haixia; Rehman, Jalees; Tang, Haiyang; Wary, Kishore; Mittal, Manish; Chatturvedi, Pallavi; Zhao, Youyang; Komorova, Yulia A.; Vogel, Stephen M.; Malik, Asrar B.

    2015-01-01

    Vascular endothelial barrier dysfunction underlies diseases such as acute respiratory distress syndrome (ARDS), characterized by edema and inflammatory cell infiltration. The transcription factor HIF2α is highly expressed in vascular endothelial cells (ECs) and may regulate endothelial barrier function. Here, we analyzed promoter sequences of genes encoding proteins that regulate adherens junction (AJ) integrity and determined that vascular endothelial protein tyrosine phosphatase (VE-PTP) is a HIF2α target. HIF2α-induced VE-PTP expression enhanced dephosphorylation of VE-cadherin, which reduced VE-cadherin endocytosis and thereby augmented AJ integrity and endothelial barrier function. Mice harboring an EC-specific deletion of Hif2a exhibited decreased VE-PTP expression and increased VE-cadherin phosphorylation, resulting in defective AJs. Mice lacking HIF2α in ECs had increased lung vascular permeability and water content, both of which were further exacerbated by endotoxin-mediated injury. Treatment of these mice with Fg4497, a prolyl hydroxylase domain 2 (PHD2) inhibitor, activated HIF2α-mediated transcription in a hypoxia-independent manner. HIF2α activation increased VE-PTP expression, decreased VE-cadherin phosphorylation, promoted AJ integrity, and prevented the loss of endothelial barrier function. These findings demonstrate that HIF2α enhances endothelial barrier integrity, in part through VE-PTP expression and the resultant VE-cadherin dephosphorylation-mediated assembly of AJs. Moreover, activation of HIF2α/VE-PTP signaling via PHD2 inhibition has the potential to prevent the formation of leaky vessels and edema in inflammatory diseases such as ARDS. PMID:25574837

  3. Acute Esophagus Toxicity in Lung Cancer Patients After Intensity Modulated Radiation Therapy and Concurrent Chemotherapy

    SciTech Connect

    Kwint, Margriet; Uyterlinde, Wilma; Nijkamp, Jasper; Chen, Chun; Bois, Josien de; Sonke, Jan-Jakob; Heuvel, Michel van den; Knegjens, Joost; Herk, Marcel van; Belderbos, Jose

    2012-10-01

    Purpose: The purpose of this study was to investigate the dose-effect relation between acute esophageal toxicity (AET) and the dose-volume parameters of the esophagus after intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for patients with non-small cell lung cancer (NSCLC). Patients and Methods: One hundred thirty-nine patients with inoperable NSCLC treated with IMRT and concurrent chemotherapy were prospectively analyzed. The fractionation scheme was 66 Gy in 24 fractions. All patients received concurrently a daily dose of cisplatin (6 mg/m Superscript-Two ). Maximum AET was scored according to Common Toxicity Criteria 3.0. Dose-volume parameters V5 to V70, D{sub mean} and D{sub max} of the esophagus were calculated. A logistic regression analysis was performed to analyze the dose-effect relation between these parameters and grade {>=}2 and grade {>=}3 AET. The outcome was compared with the clinically used esophagus V35 prediction model for grade {>=}2 after radical 3-dimensional conformal radiation therapy (3DCRT) treatment. Results: In our patient group, 9% did not experience AET, and 31% experienced grade 1 AET, 38% grade 2 AET, and 22% grade 3 AET. The incidence of grade 2 and grade 3 AET was not different from that in patients treated with CCRT using 3DCRT. The V50 turned out to be the most significant dosimetric predictor for grade {>=}3 AET (P=.012). The derived V50 model was shown to predict grade {>=}2 AET significantly better than the clinical V35 model (P<.001). Conclusions: For NSCLC patients treated with IMRT and concurrent chemotherapy, the V50 was identified as most accurate predictor of grade {>=}3 AET. There was no difference in the incidence of grade {>=}2 AET between 3DCRT and IMRT in patients treated with concurrent chemoradiation therapy.

  4. Lung ventilation strategies for acute respiratory distress syndrome: a systematic review and network meta-analysis.

    PubMed

    Wang, Changsong; Wang, Xiaoyang; Chi, Chunjie; Guo, Libo; Guo, Lei; Zhao, Nana; Wang, Weiwei; Pi, Xin; Sun, Bo; Lian, Ailing; Shi, Jinghui; Li, Enyou

    2016-01-01

    To identify the best lung ventilation strategy for acute respiratory distress syndrome (ARDS), we performed a network meta-analysis. The Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, CINAHL, and the Web of Science were searched, and 36 eligible articles were included. Compared with higher tidal volumes with FiO2-guided lower positive end-expiratory pressure [PEEP], the hazard ratios (HRs) for mortality were 0.624 (95% confidence interval (CI) 0.419-0.98) for lower tidal volumes with FiO2-guided lower PEEP and prone positioning and 0.572 (0.34-0.968) for pressure-controlled ventilation with FiO2-guided lower PEEP. Lower tidal volumes with FiO2-guided higher PEEP and prone positioning had the greatest potential to reduce mortality, and the possibility of receiving the first ranking was 61.6%. Permissive hypercapnia, recruitment maneuver, and low airway pressures were most likely to be the worst in terms of all-cause mortality. Compared with higher tidal volumes with FiO2-guided lower PEEP, pressure-controlled ventilation with FiO2-guided lower PEEP and lower tidal volumes with FiO2-guided lower PEEP and prone positioning ventilation are associated with lower mortality in ARDS patients. Lower tidal volumes with FiO2-guided higher PEEP and prone positioning ventilation and lower tidal volumes with pressure-volume (P-V) static curve-guided individual PEEP are potential optimal strategies for ARDS patients. PMID:26955891

  5. The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema.

    PubMed

    Schoene, R B; Swenson, E R; Pizzo, C J; Hackett, P H; Roach, R C; Mills, W J; Henderson, W R; Martin, T R

    1988-06-01

    High-altitude pulmonary edema (HAPE), a severe form of altitude illness that can occur in young healthy individuals, is a noncardiogenic form of edema that is associated with high concentrations of proteins and cells in bronchoalveolar lavage (BAL) fluid (Schoene et al., J. Am. Med. Assoc. 256: 63-69, 1986). We hypothesized that acute mountain sickness (AMS) in which gas exchange is impaired to a milder degree is a precursor to HAPE. We therefore performed BAL with 0.89% NaCl by fiberoptic bronchoscopy in eight subjects at 4,400 m (barometric pressure = 440 Torr) on Mt. McKinley to evaluate the cellular and biochemical responses of the lung at high altitude. The subjects included one healthy control (arterial O2 saturation = 83%), three climbers with HAPE (mean arterial O2 saturation = 55.0 +/- 5.0%), and four with AMS (arterial O2 saturation = 70.0 +/- 2.4%). Cell counts and differentials were done immediately on the BAL fluid, and the remainder was frozen for protein and biochemical analysis to be performed later. The results of this and of the earlier study mentioned above showed that the total leukocyte count (X10(5)/ml) in BAL fluid was 3.5 +/- 2.0 for HAPE, 0.9 +/- 4.0 for AMS, and 0.7 +/- 0.6 for controls, with predominantly alveolar macrophages in HAPE. The total protein concentration (mg/dl) was 616.0 +/- 3.3 for HAPE, 10.4 +/- 8.3 for AMS, and 12.0 +/- 3.4 for controls, with both large- (immunoglobulin M) and small- (albumin) molecular-weight proteins present in HAPE.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3403445

  6. Fever Is Associated with Delayed Ventilator Liberation in Acute Lung Injury

    PubMed Central

    Dowdy, David W.; Harrington, Thelma; Chandolu, Satish; Dinglas, Victor D.; Shah, Nirav G.; Colantuoni, Elizabeth; Mendez-Tellez, Pedro A.; Shanholtz, Carl; Hasday, Jeffrey D.; Needham, Dale M.

    2013-01-01

    Background: Acute lung injury (ALI) is characterized by inflammation, leukocyte activation, neutrophil recruitment, endothelial dysfunction, and epithelial injury, which are all affected by fever. Fever is common in the intensive care unit, but the relationship between fever and outcomes in ALI has not yet been studied. We evaluated the association of temperature dysregulation with time to ventilator liberation, ventilator-free days, and in-hospital mortality. Methods: Analysis of a prospective cohort study, which recruited consecutive patients with ALI from 13 intensive care units at four hospitals in Baltimore, Maryland. The relationship of fever and hypothermia with ventilator liberation was assessed with a Cox proportional hazards model. We evaluated the association of temperature during the first 3 days after ALI with ventilator-free days, using multivariable linear regression models, and the association with mortality was evaluated by robust Poisson regression. Measurements and Main Results: Of 450 patients, only 12% were normothermic during the first 3 days after ALI onset. During the first week post-ALI, each additional day of fever resulted in a 33% reduction in the likelihood of successful ventilator liberation (95% confidence interval [CI] for adjusted hazard ratio, 0.57 to 0.78; P < 0.001). Hypothermia was independently associated with decreased ventilator-free days (hypothermia during each of the first 3 d: reduction of 5.58 d, 95% CI: –9.04 to –2.13; P = 0.002) and increased mortality (hypothermia during each of the first 3 d: relative risk, 1.68; 95% CI, 1.06 to 2.66; P = 0.03). Conclusions: Fever and hypothermia are associated with worse clinical outcomes in ALI, with fever being independently associated with delayed ventilator liberation. PMID:24024608

  7. Lung ventilation strategies for acute respiratory distress syndrome: a systematic review and network meta-analysis

    PubMed Central

    Wang, Changsong; Wang, Xiaoyang; Chi, Chunjie; Guo, Libo; Guo, Lei; Zhao, Nana; Wang, Weiwei; Pi, Xin; Sun, Bo; Lian, Ailing; Shi, Jinghui; Li, Enyou

    2016-01-01

    To identify the best lung ventilation strategy for acute respiratory distress syndrome (ARDS), we performed a network meta-analysis. The Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, CINAHL, and the Web of Science were searched, and 36 eligible articles were included. Compared with higher tidal volumes with FiO2-guided lower positive end-expiratory pressure [PEEP], the hazard ratios (HRs) for mortality were 0.624 (95% confidence interval (CI) 0.419–0.98) for lower tidal volumes with FiO2-guided lower PEEP and prone positioning and 0.572 (0.34–0.968) for pressure-controlled ventilation with FiO2-guided lower PEEP. Lower tidal volumes with FiO2-guided higher PEEP and prone positioning had the greatest potential to reduce mortality, and the possibility of receiving the first ranking was 61.6%. Permissive hypercapnia, recruitment maneuver, and low airway pressures were most likely to be the worst in terms of all-cause mortality. Compared with higher tidal volumes with FiO2-guided lower PEEP, pressure-controlled ventilation with FiO2-guided lower PEEP and lower tidal volumes with FiO2-guided lower PEEP and prone positioning ventilation are associated with lower mortality in ARDS patients. Lower tidal volumes with FiO2-guided higher PEEP and prone positioning ventilation and lower tidal volumes with pressure-volume (P–V) static curve-guided individual PEEP are potential optimal strategies for ARDS patients. PMID:26955891

  8. Effect of inhaled nitric oxide on pulmonary hemodynamics after acute lung injury in dogs

    SciTech Connect

    Romand, J.A.; Pinsky, M.R.; Firestone, L.; Zar, H.A.; Lancaster, J.R. Jr. )

    1994-03-01

    Increased pulmonary vascular resistance (PVR) and mismatch in ventilation-to-perfusion ratio characterize acute lung injury (ALI). Pulmonary arterial pressure (Ppa) decreases when nitric oxide (NO) is inhaled during hypoxic pulmonary vasoconstriction (HPV); thus NO inhalation may reduce PVR and improve gas exchange in ALI. The authors studied the hemodynamic and gas exchange effects of NO inhalation during HPV and then ALI in eight anesthetized open-chest mechanically ventilated dogs. Right atrial pressure, Ppa, and left ventricular and arterial pressures were measured, and cardiac output was estimated by an aortic flow probe. Shunt and dead space were also estimated. The effect of 5-min exposures to 0, 17, 28, 47, and 0 ppm inhaled NO was recorded during hyperoxia, hypoxia, and oleic acid-induced ALI. During ALI, partial [beta]-adrenergic blockage (propanolol, 0.15 mg/kg iv) was induced and 74 ppm NO was inhaled. Nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) levels were measured. During hyperoxia, NO inhalation had no measurable effects. Hypoxia increased Ppa and calculated PVR, both of which decreased with 17 ppm NO. ALI decreased arterial Po[sub 2] and increased airway pressure, shunt, and dead space ventilation. Ppa and PVR were greater during ALI than during hyperoxia. NO inhalation had no measurable effect during ALI before or after [beta]-adrenergic blockage. MetHb remained low, and NO-Hb was unmeasurable. Bolus infusion of nitroglycerin (15 [mu]g) induced an immediate decrease in Ppa and PVR during ALI. Short-term NO inhalation does not affect PVR or gas exchange in dogs with oleic acid-induced ALI, nor does it increase NO-Hb or MetHb. In contrast, NO can diminish hypoxia-induced elevations in pulmonary vascular tone. These data suggest that NO inhalation selectively dilates the pulmonary circulation and specifically reduces HPV but not oleic acid-induced increases in pulmonary vasomotor tone. 28 refs., 3 figs., 2 tabs.

  9. [Acute and subacute chemical pneumonitis].

    PubMed

    Andujar, P; Nemery, B

    2009-10-01

    Acute or subacute chemical-induced lung injury is rarely compound specific and is most often caused by an accidental occupational, domestic or environmental exposure to an inhaled chemical agent. The industrial disaster that happened in Bhopal in 1984, accidental poisoning with chlorine and petroleum hydrocarbons and also vesicant gases used during conflicts, are specific examples. Rarely, a chemical agent can cause lung damage by being ingested and reaching the lung through the systemic circulation (for example accidental or deliberate paraquat ingestion). Household accidents should not be underestimated. An important cause of household accidents is chlorine inhalation resulting from mixing bleach with acids such as the scale removers used to clean toilets. Chemical agents can provoke direct and/or indirect damage to the respiratory tract. The acute or subacute clinical manifestations resulting from inhalation of chemical agents are very varied and include inhalation fevers, acute non-cardiogenic pulmonary oedema, adult respiratory distress syndrome, reactive airways dysfunction syndrome and acute or subacute pneumonitis. The site and the severity of chemical-induced respiratory damage caused by inhaled chemical agents depend mainly on the nature and the amount of the agent inhaled. The immediate and long-term prognosis and possible sequelae are also variable. This review excludes infectious or immunologically induced acute respiratory diseases. PMID:19953031

  10. Preventive effects of dexmedetomidine on the liver in a rat model of acid-induced acute lung injury.

    PubMed

    Sen, Velat; Güzel, Abdulmenap; Şen, Hadice Selimoğlu; Ece, Aydın; Uluca, Unal; Söker, Sevda; Doğan, Erdal; Kaplan, İbrahim; Deveci, Engin

    2014-01-01

    The aim of this study was to examine whether dexmedetomidine improves acute liver injury in a rat model. Twenty-eight male Wistar albino rats weighing 300-350 g were allocated randomly to four groups. In group 1, normal saline (NS) was injected into the lungs and rats were allowed to breathe spontaneously. In group 2, rats received standard ventilation (SV) in addition to NS. In group 3, hydrochloric acid was injected into the lungs and rats received SV. In group 4, rats received SV and 100 µg/kg intraperitoneal dexmedetomidine before intratracheal HCl instillation. Blood samples and liver tissue specimens were examined by biochemical, histopathological, and immunohistochemical methods. Acute lung injury (ALI) was found to be associated with increased malondialdehyde (MDA), total oxidant activity (TOA), oxidative stress index (OSI), and decreased total antioxidant capacity (TAC). Significantly decreased MDA, TOA, and OSI levels and significantly increased TAC levels were found with dexmedetomidine injection in group 4 (P < 0.05). The highest histologic injury scores were detected in group 3. Enhanced hepatic vascular endothelial growth factor (VEGF) expression and reduced CD68 expression were found in dexmedetomidine group compared with the group 3. In conclusion, the presented data provide the first evidence that dexmedetomidine has a protective effect on experimental liver injury induced by ALI. PMID:25165710

  11. The efficacy of oral glutamine in prevention of acute radiotherapy-induced esophagitis in patients with lung cancer

    PubMed Central

    Tutanc, Oznur Donmez; Aydogan, Akin; Sunbul, Ahmet Taner; Zincircioglu, Seyit Burhanedtin; Alpagat, Gulistan; Erden, Ersin Sukru

    2013-01-01

    Aim of the study This study explores the efficacy of oral glutamine in the prevention of acute radiotherapy-induced esophagitis in patients with lung cancer who are treated with thoracic radiotherapy. Material and methods This study was planned as a retrospective randomized experimental study. Forty-six patients with lung cancer, who were treated and kept under control between January 2008 and January 2010, were included in the study by the Department of Radiation Oncology, Faculty of Medicine, Dicle University. The patients were divided into two groups. The first group (n = 21) was given prophylactic oral powder glutamine (daily 30 g), while the second group (n = 25) was not given oral glutamine. Results There were 21 patients in Group 1 (45.7%) and 25 patients in Group 2 (54.3%). No significant statistical difference was observed between the two groups in terms of age, gender, stage, histopathological type, treatment choice, received radiation doses, esophagus length in RT field, or location of the tumor (p > 0.05). A significant statistical difference was observed between the glutamine-supplemented group (first group) and the glutamine-free group (second group) according to the grade of esophagitis (p < 0.0001). Conclusions In our retrospective randomized experimental study, we determined that the severity of acute radiotherapy-induced esophagitis might be decreased with oral glutamine in patients with lung cancer who were treated with thoracic radiotherapy. PMID:24592140

  12. Genetic variant associations of human SP-A and SP-D with acute and chronic lung injury

    PubMed Central

    Silveyra, Patricia; Floros, Joanna

    2013-01-01

    Pulmonary surfactant, a lipoprotein complex, maintains alveolar integrity and plays an important role in lung host defense, and control of inflammation. Altered inflammatory processes and surfactant dysfunction are well described events that occur in patients with acute or chronic lung disease that can develop secondary to a variety of insults. Genetic variants of surfactant proteins, including single nucleotide polymorphisms, haplotypes, and other genetic variations have been associated with acute and chronic lung disease throughout life in several populations and study groups. The hydrophilic surfactant proteins SP-A and SP-D, also known as collectins, in addition to their surfactant-related functions, are important innate immunity molecules as these, among others, exhibit the ability to bind and enhance clearance of a wide range of pathogens and allergens. This review focuses on published association studies of human surfactant proteins A and D genetic polymorphisms with respiratory, and non-respiratory diseases in adults, children, and newborns. The potential role of genetic variations in pulmonary disease or pathogenesis is discussed following an evaluation, and comparison of the available literature. PMID:22201752

  13. Effects of Xuanbai Chengqi decoction on lung compliance for patients with exogenous pulmonary acute respiratory distress syndrome

    PubMed Central

    Mao, Zhengrong; Wang, Haifeng

    2016-01-01

    Objective To observe the effects of Xuanbai Chengqi decoction on lung compliance for patients with exogenous pulmonary acute respiratory distress syndrome. Subjects and methods A total of 53 patients with exogenous pulmonary acute respiratory distress syndrome, who were admitted to the intensive care unit of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine from March 2009 to February 2013, were selected. They were randomly divided into the treatment group (25 cases) and the control group (28 cases). Both the groups were treated with conventional treatment and lung-protective ventilation strategy; apart from these, enema therapy with Xuanbai Chengqi decoction was given to the treatment group. Meanwhile, static lung compliance, dynamic lung compliance, peak airway pressure, plateau pressure, and positive end-expiratory pressure (PEEP) for patients in both the groups were observed and recorded at 24, 48, and 72 hours after the drug was used. Moreover, variations in the duration of parenteral nutrition, incidence rate of complications, and case fatality rate in patients after treatment were recorded. Results For patients in the treatment group, at 48 and 72 hours after treatment, the static lung compliance and dynamic lung compliance were significantly higher than those in the control group, while plateau pressure, peak airway pressure, and PEEP were significantly lower than those before treatment. At the same time, PEEP for patients in the treatment group at 72 hours after treatment was remarkably lower than that in the control group, showing significant difference (P<0.05). The duration of parenteral nutrition in the treatment group was significantly shorter than that in the control group (P<0.05). Both the incidence rate and the fatality rate of complications, such as abdominal distension and ventilator-associated pneumonia, for patients in the treatment group were distinctly smaller than those in the control group (P<0

  14. Parasite Burden and CD36-Mediated Sequestration Are Determinants of Acute Lung Injury in an Experimental Malaria Model

    PubMed Central

    Lovegrove, Fiona E.; Gharib, Sina A.; Peña-Castillo, Lourdes; Patel, Samir N.; Ruzinski, John T.; Hughes, Timothy R.

    2008-01-01

    Although acute lung injury (ALI) is a common complication of severe malaria, little is known about the underlying molecular basis of lung dysfunction. Animal models have provided powerful insights into the pathogenesis of severe malaria syndromes such as cerebral malaria (CM); however, no model of malaria-induced lung injury has been definitively established. This study used bronchoalveolar lavage (BAL), histopathology and gene expression analysis to examine the development of ALI in mice infected with Plasmodium berghei ANKA (PbA). BAL fluid of PbA-infected C57BL/6 mice revealed a significant increase in IgM and total protein prior to the development of CM, indicating disruption of the alveolar–capillary membrane barrier—the physiological hallmark of ALI. In contrast to sepsis-induced ALI, BAL fluid cell counts remained constant with no infiltration of neutrophils. Histopathology showed septal inflammation without cellular transmigration into the alveolar spaces. Microarray analysis of lung tissue from PbA-infected mice identified a significant up-regulation of expressed genes associated with the gene ontology categories of defense and immune response. Severity of malaria-induced ALI varied in a panel of inbred mouse strains, and development of ALI correlated with peripheral parasite burden but not CM susceptibility. Cd36−/− mice, which have decreased parasite lung sequestration, were relatively protected from ALI. In summary, parasite burden and CD36-mediated sequestration in the lung are primary determinants of ALI in experimental murine malaria. Furthermore, differential susceptibility of mouse strains to malaria-induced ALI and CM suggests that distinct genetic determinants may regulate susceptibility to these two important causes of malaria-associated morbidity and mortality. PMID:18483551

  15. Distending Pressure Did Not Activate Acute Phase or Inflammatory Responses in the Airways and Lungs of Fetal, Preterm Lambs

    PubMed Central

    Petersen, Rebecca Y.; Royse, Emily; Kemp, Matthew W.; Miura, Yuichiro; Noe, Andres; Jobe, Alan H.; Hillman, Noah H.

    2016-01-01

    Background Mechanical ventilation at birth causes airway injury and lung inflammation in preterm sheep. Continuous positive airway pressure (CPAP) is being increasingly used clinically to transition preterm infants at birth. Objective To test if distending pressures will activate acute phase reactants and inflammatory changes in the airways of fetal, preterm lambs. Methods The head and chest of fetal lambs at 128±1 day GA were surgically exteriorized. With placental circulation intact, fetal lambs were then randomized to one of five 15 minute interventions: PEEP of 0, 4, 8, 12, or 16 cmH2O. Recruitment volumes were recorded. Fetal lambs remained on placental support for 30 min after the intervention. The twins of each 0 cmH2O animal served as controls. Fetal lung fluid (FLF), bronchoalveolar lavage fluid (BAL), right mainstem bronchi and peripheral lung tissue were evaluated for inflammation. Results Recruitment volume increased from 0.4±0.04 mL/kg at 4 cmH2O to 2.4±0.3 mL/kg at 16 cmH2O. The lambs were surfactant deficient, and all pressures were below the opening inflection pressure on pressure-volume curve. mRNA expression of early response genes and pro-inflammatory cytokines did not increase in airway tissue or lung tissue at any pressure compared to controls. FLF and BAL also did not have increases in early response proteins. No histologic changes or Egr-1 activation was present at the pressures used. Conclusion Distending pressures as high as 16 cmH2O did not recruit lung volume at birth and did not increase markers of injury in the lung or airways in non-breathing preterm fetal sheep. PMID:27463520

  16. Regulatory effects of hydrogen sulfide on alveolar epithelial cell endoplasmic reticulum stress in rats with acute lung injury

    PubMed Central

    Liu, Zhi-wei; Wang, Hai-ying; Guan, Lan; Zhao, Bin

    2015-01-01

    BACKGROUND: The present study was undertaken to examine the regulatory effect of hydrogen sulfide (H2S) on endoplasmic reticulum stress in alveolar epithelial cells of rats with acute lung injury (ALI) induced by oleic acid (OA). METHODS: Seventy-two male Sprague Dawley (SD) rats were divided into control group, oleic acid-induced ALI group (OA group), oleic acid-induced ALI with sodium hydrosulfide (NaHS) pretreatment group (OA+NaHS group), and sodium hydrosulfide treatment group (NaHS group). Rats of each group were further subdivided into 3 subgroups. Index of quantitative assessment of histological lung injury (IQA), wet/dry weight ratio (W/D) and H2S level of lung tissues were measured. The expressions of endoplasmic reticulum stress markers including glucose-regulated protein 78 (GRP78) and α-subunit of eukaryotic translation initiation factor-2 (elF2α) in lung tissues were measured by immunohistochemical staining and Western blotting. RESULTS: The IQA score and W/D ratio of lung tissues at the three time points significantly increased in rats injected with OA, but significantly decreased in other rats injected with OA and NaHS. The level of H2S in lung tissue at the three time points significantly decreased in rats injected with OA, but significantly increased in other rats injected with both OA and NaHS. GRP78 and elF2α decreased in rats injected with OA, but increased in other rats injected with both OA and NaHS, especially at 4-hour and 6-hour time points. CONCLUSION: The results suggested that H2S could promote alveolar epithelial cell endoplasmic reticulum stress in rats with ALI. PMID:25802570

  17. Combined treatment with bone marrow mesenchymal stem cells and methylprednisolone in paraquat-induced acute lung injury

    PubMed Central

    2013-01-01

    Background To evaluate the efficacy of combined treatment with bone marrow mesenchymal stem cell (BMSC) transplantation and methylprednisolone (MP) to treat paraquat (PQ)-induced acute lung injury. Materials and methods A total of 102 female rats were randomly divided into five groups: PQ, BMSC, MP, BMSC + MP and normal control. After 14 days of PQ poisoning, the survival of rats, wet/dry weight ratio of lung tissue, serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-10, malondialdehyde (MDA) and superoxidase dismutase (SOD), and the expression of nuclear factor (NF)-кB p65 in lung tissue were determined. Results Rats in BMSC and BMSC + MP groups survived. BMSC transplantation significantly decreased the wet/dry weight ratio of lung tissue, down-regulated NF-кB p65 expression in lung tissue, lowered serum levels of TNF-α, IL-1β, IL-6 and MDA, and increased serum levels of IL-10 and SOD. These changes were particularly significant on days 7–14 after PQ poisoning. The above changes were more significant in the MP group on days 1–3 after PQ poisoning, compared with those of the BMSC group. However, the BMSC + MP group showed more significant changes on days 1–14 after PQ poisoning than those of both BMSC and MP groups. Conclusions MP inhibits the inflammatory response, reduces the products of lipid peroxidation and promotes survival of transplanted BMSC, thus improving the intermediate and longer term efficacy of BMSC transplantation for treatment of PQ-induced lung injury. PMID:23902576

  18. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice.

    PubMed

    Zhu, Ying-Gang; Feng, Xiao-Mei; Abbott, Jason; Fang, Xiao-Hui; Hao, Qi; Monsel, Antoine; Qu, Jie-Ming; Matthay, Michael A; Lee, Jae W

    2014-01-01

    We previously found that human mesenchymal stem cells (MSC) or its conditioned medium restored lung protein permeability and reduced alveolar inflammation following Escherichia coli endotoxin-induced acute lung injury (ALI) in an ex vivo perfused human lung in part through the secretion of soluble factors such as keratinocyte growth factor (KGF). Recently, MSC were found to release microvesicles (MVs) that were biologically active because of the presence of mRNA or miRNA with reparative properties. MVs are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes. These studies were designed to determine if MVs released by human bone marrow derived MSCs would be effective in restoring lung protein permeability and reducing inflammation in E. coli endotoxin-induced ALI in C57BL/6 mice. The intratracheal instillation of MVs improved several indices of ALI at 48 hours. Compared to endotoxin-injured mice, MVs reduced extravascular lung water by 43% and reduced total protein levels in the bronchoalveolar lavage (BAL) fluid by 35%, demonstrating a reduction in pulmonary edema and lung protein permeability. MVs also reduced the influx of neutrophils and macrophage inflammatory protein-2 levels in the BAL fluid by 73% and 49%, respectively, demonstrating a reduction in inflammation. KGF siRNA-pretreatment of MSC partially eliminated the therapeutic effects of MVs released by MSCs, suggesting that KGF protein expression was important for the underlying mechanism. In summary, human MSC-derived MVs were therapeutically effective following E. coli endotoxin-induced ALI in mice in part through the expression of KGF mRNA in the injured alveolus. PMID:23939814

  19. Baclofen, a GABABR Agonist, Ameliorates Immune-Complex Mediated Acute Lung Injury by Modulating Pro-Inflammatory Mediators

    PubMed Central

    Jin, Shunying; Merchant, Michael L.; Ritzenthaler, Jeffrey D.; McLeish, Kenneth R.; Lederer, Eleanor D.; Torres-Gonzalez, Edilson; Fraig, Mostafa; Barati, Michelle T.; Lentsch, Alex B.; Roman, Jesse; Klein, Jon B.; Rane, Madhavi J.

    2015-01-01

    Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC) deposition-induced acute lung injury (ALI). Components of gamma amino butyric acid (GABA) signaling, including GABA B receptor 2 (GABABR2), GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP), in the bronchoalveolar lavage fluid (BALF). Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK pho